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Recombinant Therapeutic Proteins for Drug Delivery

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 40446

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Prof. Dr. Masaki Otagiri

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Guest Editor

Drug Delivery Research Institute, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
Interests: structural and functional analysis of plasma proteins for medical and pharmaceutical applications

Dr. Victor Chuang

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Guest Editor

School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Malaysia
Interests: functionalization of plasma proteins for pharmaceutical applications
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Recombinant therapeutic proteins have gained enormous importance for clinical applications over the past ten years, so much so that they have replaced the original animal-derived version used in medicine. There are two clusters of recombinant proteins: human recombinants that largely replaced animal or harvested from human types, and human recombinants with recombination as their only source. Recombinant proteins are produced through recombinant DNA technology, which involves inserting the gene encoding the protein into expression systems such as bacteria, yeast, or mammalian cells cultures. They include but are not limited to recombinant hormones, interferons, interleukins, hematopoietic growth factors, tumor necrosis factors, blood-clotting factors, thrombolytic drugs, enzymes, monoclonal antibodies, and vaccines. Protein engineering has brought forth a good deal of products with application-specific properties obtained by fusion, mutation, or deletion. Novel, engineered expression systems and integrated technology platforms hold enormous potential for future applications where challenges, primarily related to the pharmacokinetics of artificial recombinant protein drugs, can be overcome by diverging from the original. The development of recombinant proteins capable of entering a cell is a major breakthrough. Such drugs open up completely new opportunities by targeting intracellular mechanisms or by substituting intracellularly operating enzymes. As with other drugs, the efficacy and safety of therapeutic proteins have to be validated in clinical studies, and superiority over available products has to be proven. The Special Issue of Pharmaceutics on "Recombinant Therapeutic Proteins for Drug Delivery" will address diverse areas related to molecular design for drug delivery, targeting and functionalization, genetic manipulation, expression, purification, characterization, post-translational modifications, formulation, safety, stability and efficacy studies, as well as opportunities for the biopharmaceutical industry. Original research papers, communications, or review articles on any of these aspects are welcome for this Special Issue.

Prof. Dr. Masaki Otagiri
Dr. Victor Chuang
Guest Editors

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Keywords

antibodies
antibody fragments
cytokines
drug delivery
enzymes
expression systems
formulation
functionalization
genetic fusion
glycosylation
growth factors
hormones
mutant
nanomedicine
nanotechnology
ortholog proteins
pharmacokinetics
post-translational modifications
protein engineering
receptors
recombinant DNA
safety
stability
targeting
therapeutics
transcription factors
wild type

Published Papers (10 papers)

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Research

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23 pages, 12730 KiB

Open AccessArticle

Glycan Profile Analysis of Engineered Trastuzumab with Rationally Added Glycosylation Sequons Presents Significantly Increased Glycan Complexity

by Esteban Cruz, Vicki Sifniotis, Zeynep Sumer-Bayraktar, Mouhamad Reslan, Lorna Wilkinson-White, Stuart Cordwell and Veysel Kayser

Pharmaceutics 2021, 13(11), 1747; https://doi.org/10.3390/pharmaceutics13111747 - 20 Oct 2021

Cited by 2 | Viewed by 2181

Abstract

Protein aggregation constitutes a recurring complication in the manufacture and clinical use of therapeutic monoclonal antibodies (mAb) and mAb derivatives. Antibody aggregates can reduce production yield, cause immunogenic reactions, decrease the shelf-life of the pharmaceutical product and impair the capacity of the antibody monomer to bind to its cognate antigen. A common strategy to tackle protein aggregation involves the identification of surface-exposed aggregation-prone regions (APR) for replacement through protein engineering. It was shown that the insertion of N-glycosylation sequons on amino acids proximal to an aggregation-prone region can increase the physical stability of the protein by shielding the APR, thus preventing self-association of antibody monomers. We recently implemented this approach in the Fab region of full-size adalimumab and demonstrated that the thermodynamic stability of the Fab domain increases upon N-glycosite addition. Previous experimental data reported for this technique have lacked appropriate confirmation of glycan occupancy and structural characterization of the ensuing glycan profile. Herein, we mutated previously identified candidate positions on the Fab domain of Trastuzumab and employed tandem mass spectrometry to confirm attachment and obtain a detailed N-glycosylation profile of the mutants. The Trastuzumab glycomutants displayed a glycan profile with significantly higher structural heterogeneity compared to the HEK Trastuzumab antibody, which contains a single N-glycosylation site per heavy chain located in the CH2 domain of the Fc region. These findings suggest that Fab N-glycosites have higher accessibility to enzymes responsible for glycan maturation. Further, we have studied effects on additional glycosylation on protein stability via accelerated studies by following protein folding and aggregation propensities and observed that additional glycosylation indeed enhances physical stability and prevent protein aggregation. Our findings shed light into mAb glycobiology and potential implications in the application of this technique for the development of “biobetter” antibodies. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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21 pages, 4363 KiB

Open AccessArticle

Intracellular Delivery of Active Proteins by Polyphosphazene Polymers

by Bareera Qamar, Melani Solomon, Alexander Marin, Thomas R. Fuerst, Alexander K. Andrianov and Silvia Muro

Pharmaceutics 2021, 13(2), 249; https://doi.org/10.3390/pharmaceutics13020249 - 10 Feb 2021

Cited by 9 | Viewed by 3142

Abstract

Achieving intracellular delivery of protein therapeutics within cells remains a significant challenge. Although custom formulations are available for some protein therapeutics, the development of non-toxic delivery systems that can incorporate a variety of active protein cargo and maintain their stability, is a topic of great relevance. This study utilized ionic polyphosphazenes (PZ) that can assemble into supramolecular complexes through non-covalent interactions with different types of protein cargo. We tested a PEGylated graft copolymer (PZ-PEG) and a pyrrolidone containing linear derivative (PZ-PYR) for their ability to intracellularly deliver FITC-avidin, a model protein. In endothelial cells, PZ-PYR/protein exhibited both faster internalization and higher uptake levels than PZ-PEG/protein, while in cancer cells both polymers achieved similar uptake levels over time, although the internalization rate was slower for PZ-PYR/protein. Uptake was mediated by endocytosis through multiple mechanisms, PZ-PEG/avidin colocalized more profusely with endo-lysosomes, and PZ-PYR/avidin achieved greater cytosolic delivery. Consequently, a PZ-PYR-delivered anti-F-actin antibody was able to bind to cytosolic actin filaments without needing cell permeabilization. Similarly, a cell-impermeable Bax-BH3 peptide known to induce apoptosis, decreased cell viability when complexed with PZ-PYR, demonstrating endo-lysosomal escape. These biodegradable PZs were non-toxic to cells and represent a promising platform for drug delivery of protein therapeutics. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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15 pages, 1790 KiB

Open AccessArticle

Development of Processes for Recombinant L-Asparaginase II Production by Escherichia coli Bl21 (De3): From Shaker to Bioreactors

by Thaís Barros, Larissa Brumano, Marcela Freitas, Adalberto Pessoa, Junior, Nádia Parachin and Pérola O. Magalhães

Pharmaceutics 2021, 13(1), 14; https://doi.org/10.3390/pharmaceutics13010014 - 24 Dec 2020

Cited by 4 | Viewed by 4055

Abstract

Since 1961, L-asparaginase has been used to treat patients with acute lymphocytic leukemia. It rapidly depletes the plasma asparagine and deprives the blood cells of this circulating amino acid, essential for the metabolic cycles of cells. In the search for viable alternatives to produce L-asparaginase, this work aimed to produce this enzyme from Escherichia coli in a shaker and in a 3 L bioreactor. Three culture media were tested: defined, semi-defined and complex medium. L-asparaginase activity was quantified using the β-hydroxamate aspartic acid method. The defined medium provided the highest L-asparaginase activity. In induction studies, two inducers, lactose and its analog IPTG, were compared. Lactose was chosen as an inducer for the experiments conducted in the bioreactor due to its natural source, lower cost and lower toxicity. Batch and fed-batch cultures were carried out to reach high cell density and then start the induction. Batch cultivation provided a final cell concentration of 11 g L⁻¹ and fed-batch cultivation produced 69.90 g L⁻¹ of cells, which produced a volumetric activity of 43,954.79 U L⁻¹ after lactose induction. L-asparaginase was produced in a shaker and scaled up to a bioreactor, increasing 23-fold the cell concentration and thus, the enzyme productivity. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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17 pages, 2582 KiB

Open AccessArticle

Recombinant Myxoma Virus-Derived Immune Modulator M-T7 Accelerates Cutaneous Wound Healing and Improves Tissue Remodeling

by Jordan R. Yaron, Liqiang Zhang, Qiuyun Guo, Enkidia A. Awo, Michelle Burgin, Lauren N. Schutz, Nathan Zhang, Jacquelyn Kilbourne, Juliane Daggett-Vondras, Kenneth M. Lowe and Alexandra R. Lucas

Pharmaceutics 2020, 12(11), 1003; https://doi.org/10.3390/pharmaceutics12111003 - 22 Oct 2020

Cited by 11 | Viewed by 2898

Abstract

Complex dermal wounds represent major medical and financial burdens, especially in the context of comorbidities such as diabetes, infection and advanced age. New approaches to accelerate and improve, or “fine tune” the healing process, so as to improve the quality of cutaneous wound healing and management, are the focus of intense investigation. Here, we investigate the topical application of a recombinant immune modulating protein which inhibits the interactions of chemokines with glycosaminoglycans, reducing damaging or excess inflammation responses in a splinted full-thickness excisional wound model in mice. M-T7 is a 37 kDa-secreted, virus-derived glycoprotein that has demonstrated therapeutic efficacy in numerous animal models of inflammatory immunopathology. Topical treatment with recombinant M-T7 significantly accelerated wound healing when compared to saline treatment alone. Healed wounds exhibited properties of improved tissue remodeling, as determined by collagen maturation. M-T7 treatment accelerated the rate of peri-wound angiogenesis in the healing wounds with increased levels of TNF, VEGF and CD31. The immune cell response after M-T7 treatment was associated with a retention of CCL2 levels, and increased abundances of arginase-1-expressing M2 macrophages and CD4 T cells. Thus, topical treatment with recombinant M-T7 promotes a pro-resolution environment in healing wounds, and has potential as a novel treatment approach for cutaneous tissue repair. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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17 pages, 1384 KiB

Open AccessArticle

HER2-Specific Pseudomonas Exotoxin A PE25 Based Fusions: Influence of Targeting Domain on Target Binding, Toxicity, and In Vivo Biodistribution

by Haozhong Ding, Mohamed Altai, Wen Yin, Sarah Lindbo, Hao Liu, Javad Garousi, Tianqi Xu, Anna Orlova, Vladimir Tolmachev, Sophia Hober and Torbjörn Gräslund

Pharmaceutics 2020, 12(4), 391; https://doi.org/10.3390/pharmaceutics12040391 - 24 Apr 2020

Cited by 7 | Viewed by 3735

Abstract

The human epidermal growth factor receptor 2 (HER2) is a clinically validated target for cancer therapy, and targeted therapies are often used in regimens for patients with a high HER2 expression level. Despite the success of current drugs, a number of patients succumb to their disease, which motivates development of novel drugs with other modes of action. We have previously shown that an albumin binding domain-derived affinity protein with specific affinity for HER2, ADAPT₆, can be used to deliver the highly cytotoxic protein domain PE25, a derivative of Pseudomonas exotoxin A, to HER2 overexpressing malignant cells, leading to potent and specific cell killing. In this study we expanded the investigation for an optimal targeting domain and constructed two fusion toxins where a HER2-binding affibody molecule, Z_HER2:2891, or the dual-HER2-binding hybrid Z_HER2:2891-ADAPT₆ were used for cancer cell targeting. We found that both targeting domains conferred strong binding to HER2; both to the purified extracellular domain and to the HER2 overexpressing cell line SKOV3. This resulted in fusion toxins with high cytotoxic potency toward cell lines with high expression levels of HER2, with EC₅₀ values between 10 and 100 pM. For extension of the plasma half-life, an albumin binding domain was also included. Intravenous injection of the fusion toxins into mice showed a profound influence of the targeting domain on biodistribution. Compared to previous results, with ADAPT₆ as targeting domain, Z_HER2:2891 gave rise to further extension of the plasma half-life and also shifted the clearance route of the fusion toxin from the liver to the kidneys. Collectively, the results show that the targeting domain has a major impact on uptake of PE25-based fusion toxins in different organs. The results also show that PE25-based fusion toxins with high affinity to HER2 do not necessarily increase the cytotoxicity beyond a certain point in affinity. In conclusion, Z_HER2:2891 has the most favorable characteristics as targeting domain for PE25. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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13 pages, 3434 KiB

Open AccessArticle

Fab-Arm Exchange Combined with Selective Protein A Purification Results in a Platform for Rapid Preparation of Monovalent Bispecific Antibodies Directly from Culture Media

by James Steinhardt, Yanli Wu, Ryan Fleming, Ben T. Ruddle, Pooja Patel, Herren Wu, Changshou Gao and Nazzareno Dimasi

Pharmaceutics 2020, 12(1), 3; https://doi.org/10.3390/pharmaceutics12010003 - 18 Dec 2019

Cited by 7 | Viewed by 5544

Abstract

Bispecific antibody (bsAb) applications have exponentially expanded with the advent of molecular engineering strategies that have addressed many of the initial challenges, including improper light chain pairing, heterodimer purity, aggregation, and pharmacokinetics. However, the lack of high-throughput methods for the generation of monovalent bsAbs has resulted in a bottleneck that has hampered their therapeutic evaluation, as current technologies can be cost-prohibitive and impractical. To address this issue, we incorporated single-matched point mutations in the CH3 domain to recapitulate the physiological process of human IgG4 Fab-arm exchange to generate monovalent bsAbs. Furthermore, we utilized the substitutions H435R and Y436F in the CH3 domain of IgG1, which incorporates residues from human IgG3, thus ablating protein A binding. By exploiting this combination of mutations and optimizing the reduction and reoxidation conditions for Fab arm exchange, highly pure monovalent bsAbs can be rapidly purified directly from combined culture media using standard protein A purification. This methodology, reported herein for the first time, allows for the high-throughput generation of monovalent bsAbs, thus increasing the capacity for evaluating monovalent bsAb iterations for therapeutic potential. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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14 pages, 5071 KiB

Open AccessArticle

Structure and Dynamics of a Site-Specific Labeled Fc Fragment with Altered Effector Functions

by D. Travis Gallagher, Chris McCullough, Robert G. Brinson, Joomi Ahn, John P. Marino and Nazzareno Dimasi

Pharmaceutics 2019, 11(10), 546; https://doi.org/10.3390/pharmaceutics11100546 - 21 Oct 2019

Cited by 7 | Viewed by 3634

Abstract

Antibody-drug conjugates (ADCs) are a class of biotherapeutic drugs designed as targeted therapies for the treatment of cancer. Among the challenges in generating an effective ADC is the choice of an effective conjugation site on the IgG. One common method to prepare site-specific ADCs is to engineer solvent-accessible cysteine residues into antibodies. Here, we used X-ray diffraction and hydrogen-deuterium exchange mass spectroscopy to analyze the structure and dynamics of such a construct where a cysteine has been inserted after Ser 239 (Fc-239i) in the antibody heavy chain sequence. The crystal structure of this Fc-C239i variant at 0.23 nm resolution shows that the inserted cysteine structurally replaces Ser 239 and that this causes a domino-like backward shift of the local polypeptide, pushing Pro 238 out into the hinge. Proline is unable to substitute conformationally for the wild-type glycine at this position, providing a structural reason for the previously observed abolition of both FcγR binding and antibody-dependent cellular cytotoxicity. Energy estimates for the both the FcγR interface (7 kcal/mol) and for the differential conformation of proline (20 kcal/mol) are consistent with the observed disruption of FcγR binding, providing a quantifiable case where strain at a single residue appears to disrupt a key biological function. Conversely, the structure of Fc-C239i is relatively unchanged at the intersection of the CH2 and CH3 domains; the site known to be involved in binding of the neonatal Fc receptor (FcRn), and an alignment of the Fc-C239i structure with an Fc structure in a ternary Fc:FcRn:HSA (human serum albumin) complex implies that these favorable contacts would be maintained. Hydrogen deuterium exchange mass spectroscopy (HDX-MS) data further suggest a significant increase in conformational mobility for the Fc-C239i protein relative to Fc that is evident even far from the insertion site but still largely confined to the CH2 domain. Together, the findings provide a detailed structural and dynamic basis for previously observed changes in ADC functional binding to FcγR, which may guide further development of ADC designs. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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28 pages, 9278 KiB

Open AccessArticle

Targeting Cell Adhesion Molecules via Carbonate Apatite-Mediated Delivery of Specific siRNAs to Breast Cancer Cells In Vitro and In Vivo

by Maeirah Afzal Ashaie, Rowshan Ara Islam, Nur Izyani Kamaruzman, Nabilah Ibnat, Kyi Kyi Tha and Ezharul Hoque Chowdhury

Pharmaceutics 2019, 11(7), 309; https://doi.org/10.3390/pharmaceutics11070309 - 02 Jul 2019

Cited by 13 | Viewed by 3766

Abstract

While several treatment strategies are applied to cure breast cancer, it still remains one of the leading causes of female deaths worldwide. Since chemotherapeutic drugs have severe side effects and are responsible for development of drug resistance in cancer cells, gene therapy is now considered as one of the promising options to address the current treatment limitations. Identification of the over-expressed genes accounting for constitutive activation of certain pathways, and their subsequent knockdown with specific small interfering RNAs (siRNAs), could be a powerful tool in inhibiting proliferation and survival of cancer cells. In this study, we delivered siRNAs against mRNA transcripts of over-regulated cell adhesion molecules such as catenin alpha 1 (CTNNA1), catenin beta 1 (CTNNB1), talin-1 (TLN1), vinculin (VCL), paxillin (PXN), and actinin-1 (ACTN1) in human (MCF-7 and MDA-MB-231) and murine (4T1) cell lines as well as in the murine female Balb/c mice model. In order to overcome the barriers of cell permeability and nuclease-mediated degradation, the pH-sensitive carbonate apatite (CA) nanocarrier was used as a delivery vehicle. While targeting CTNNA1, CTNNB1, TLN1, VCL, PXN, and ACTN1 resulted in a reduction of cell viability in MCF-7 and MDA-MB-231 cells, delivery of all these siRNAs via carbonate apatite (CA) nanoparticles successfully reduced the cell viability in 4T1 cells. In 4T1 cells, delivery of CTNNA1, CTNNB1, TLN1, VCL, PXN, and ACTN1 siRNAs with CA caused significant reduction in phosphorylated and total AKT levels. Furthermore, reduced band intensity was observed for phosphorylated and total MAPK upon transfection of 4T1 cells with CTNNA1, CTNNB1, and VCL siRNAs. Intravenous delivery of CTNNA1 siRNA with CA nanoparticles significantly reduced tumor volume in the initial phase of the study, while siRNAs targeting CTNNB1, TLN1, VCL, PXN, and ACTN1 genes significantly decreased the tumor burden at all time points. The tumor weights at the end of the treatments were also notably smaller compared to CA. This successfully demonstrates that targeting these dysregulated genes via RNAi and by using a suitable delivery vehicle such as CA could serve as a promising therapeutic treatment modality for breast cancers. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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Review

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17 pages, 941 KiB

Open AccessReview

Strengths and Challenges of Secretory Ribonucleases as AntiTumor Agents

by Jessica Castro, Marc Ribó, Maria Vilanova and Antoni Benito

Pharmaceutics 2021, 13(1), 82; https://doi.org/10.3390/pharmaceutics13010082 - 09 Jan 2021

Cited by 7 | Viewed by 2511

Abstract

Approaches to develop effective drugs to kill cancer cells are mainly focused either on the improvement of the currently used chemotherapeutics or on the development of targeted therapies aimed at the selective destruction of cancer cells by steering specific molecules and/or enhancing the immune response. The former strategy is limited by its genotoxicity and severe side effects, while the second one is not always effective due to tumor cell heterogeneity and variability of targets in cancer cells. Between these two strategies, several approaches target different types of RNA in tumor cells. RNA degradation alters gene expression at different levels inducing cell death. However, unlike DNA targeting, it is a pleotropic but a non-genotoxic process. Among the ways to destroy RNA, we find the use of ribonucleases with antitumor properties. In the last few years, there has been a significant progress in the understanding of the mechanism by which these enzymes kill cancer cells and in the development of more effective variants. All the approaches seek to maintain the requirements of the ribonucleases to be specifically cytotoxic for tumor cells. These requirements start with the competence of the enzymes to interact with the cell membrane, a process that is critical for their internalization and selectivity for tumor cells and continue with the downstream effects mainly relying on changes in the RNA molecular profile, which are not only due to the ribonucleolytic activity of these enzymes. Although the great improvements achieved in the antitumor activity by designing new ribonuclease variants, some drawbacks still need to be addressed. In the present review, we will focus on the known mechanisms used by ribonucleases to kill cancer cells and on recent strategies to solve the shortcomings that they show as antitumor agents, mainly their pharmacokinetics. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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31 pages, 1749 KiB

Open AccessReview

Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods

by Nasir Javaid, Farzana Yasmeen and Sangdun Choi

Pharmaceutics 2019, 11(9), 441; https://doi.org/10.3390/pharmaceutics11090441 - 01 Sep 2019

Cited by 20 | Viewed by 5995

Abstract

The built-in innate immunity in the human body combats various diseases and their causative agents. One of the components of this system is Toll-like receptors (TLRs), which recognize structurally conserved molecules derived from microbes and/or endogenous molecules. Nonetheless, under certain conditions, these TLRs become hypofunctional or hyperfunctional, thus leading to a disease-like condition because their normal activity is compromised. In this regard, various small-molecule drugs and recombinant therapeutic proteins have been developed to treat the relevant diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, systemic lupus erythematosus, and allergy. Some drugs for these diseases have been clinically approved; however, their efficacy can be enhanced by conventional or targeted drug delivery systems. Certain delivery vehicles such as liposomes, hydrogels, nanoparticles, dendrimers, or cyclodextrins can be employed to enhance the targeted drug delivery. This review summarizes the TLR signaling pathway, associated diseases and their treatments, and the ways to efficiently deliver the drugs to a target site. Full article

(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)

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