Investigating Local Sequence‐Structural Attributes of Amyloidogenic Light Chain Variable Domains DOI Creative Commons
Puneet Rawat, R. Prabakaran, Divya Sharma

et al.

Proteins Structure Function and Bioinformatics, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

ABSTRACT Light chain amyloidosis is a medical condition characterized by the aggregation of misfolded antibody light chains into insoluble amyloid fibrils in target organs, causing organ dysfunction, failure, and death. Despite extensive research to understand factors contributing amyloidogenesis, accurately predicting whether given protein will form amyloids under specific conditions remains formidable challenge. In this study, we have conducted comprehensive analysis amyloidogenic tendencies within dataset containing 1828 (348 1480 non‐amyloidogenic) variable region ( V L ) sequences obtained from AL‐Base database. Physicochemical structural features often associated with aggregation, such as net charge, isoelectric point (pI), solvent‐exposed hydrophobic regions did not reveal consistent association capability chains. However, aggregation‐prone (APRs) occur higher frequencies among when compared non‐amyloidogenic ones, difference ranging 2% 15% at various relative solvent‐accessible surface area (rASA) cutoffs. We have, for first time, identified gatekeeping residues around APRs assessed their impact on amyloidogenicity The contain these gatekeeper vicinal more than ones. observed that rASA cutoff 35% optimal identifying surface‐exposed APRs, 4 Å distance APR motif(s) residues. Moreover, lambda were found surrounded fewer gatekeepers, rendering them susceptible aggregation. insights gained report significant implications understanding molecular origins light‐chain humans design aggregation‐resistant therapeutic antibodies.

Language: Английский

Exploring the next generation of antibody–drug conjugates DOI Open Access
Kyoji Tsuchikama, Yasuaki Anami, Summer Y. Y. Ha

et al.

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(3), P. 203 - 223

Published: Jan. 8, 2024

Language: Английский

Citations

184
Protein‐based Nanoparticles: From Drug Delivery to Imaging, Nanocatalysis and Protein Therapy DOI Creative Commons

Jonas Kaltbeitzel,

Peter Wich

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(44)

Published: March 14, 2023

Proteins and enzymes are versatile biomaterials for a wide range of medical applications due to their high specificity receptors substrates, degradability, low toxicity, overall good biocompatibility. Protein nanoparticles formed by the arrangement several native or modified proteins into nanometer-sized assemblies. In this review, we will focus on artificial nanoparticle systems, where main structural element not just an encapsulated payload. While under natural conditions, only certain form defined aggregates nanoparticles, chemical modifications change in physical environment can further extend pool available building blocks. This allows assembly many globular even enzymes. These advances preparation methods led emergence new generations nanosystems that beyond transport vehicles diverse applications, from multifunctional drug delivery imaging, nanocatalysis protein therapy.

Language: Английский

Citations

50
Strategies for overcoming protein and peptide instability in biodegradable drug delivery systems DOI Creative Commons
Miusi Shi, Kevin J. McHugh

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 199, P. 114904 - 114904

Published: May 30, 2023

Language: Английский

Citations

50
Reducing Immunogenicity by Design: Approaches to Minimize Immunogenicity of Monoclonal Antibodies DOI Creative Commons
Chantal T. Harris, Sivan Cohen

BioDrugs, Journal Year: 2024, Volume and Issue: 38(2), P. 205 - 226

Published: Jan. 23, 2024

Monoclonal antibodies (mAbs) have transformed therapeutic strategies for various diseases. Their high specificity to target antigens makes them ideal agents certain However, a challenge their application in clinical practice is potential risk induce unwanted immune response, termed immunogenicity. This drives the continued efforts deimmunize these protein therapeutics while maintaining pharmacokinetic properties and efficacy. Because mAbs hold central position against an array of diseases, importance conducting comprehensive immunogenicity assessment during drug development process cannot be overstated. Such necessitates employment silico, vitro, vivo evaluate mAbs. Understanding intricacies mechanisms that drive mAb crucial improving efficacy safety developing most effective determine mitigate immunogenic risk. review highlights recent advances prediction strategies, with focus on engineering used throughout reduce

Language: Английский

Citations

24
US FDA-approved therapeutic antibodies with high-concentration formulation: summaries and perspectives DOI Creative Commons

Shawn Shouye Wang,

Yifei Yan,

K. Lee Ho

et al.

Antibody Therapeutics, Journal Year: 2021, Volume and Issue: 4(4), P. 262 - 272

Published: Oct. 1, 2021

Abstract Thirty four (34) of the total US FDA approved 103 therapeutic antibody drugs, accounts for one third mAbs, are formulated with high protein concentration (100 mg/mL or above) which focus this article. The highest these mAbs is 200 mg/mL. dominant administration route subcutaneous (76%). Our analysis indicates that it may be rational to implement a platform formulation containing polysorbate, histidine and sucrose accelerate development drugs. Since 2015, approval numbers significantly increased account 76% numbers, i.e., 26 out 34 highly concentrated antibodies. Thus, we believe formulations drugs will future trend development, regardless challenges formulations.

Language: Английский

Citations

81
Instability Challenges and Stabilization Strategies of Pharmaceutical Proteins DOI Creative Commons
Mohsen Akbarian, Shu‐Hui Chen

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(11), P. 2533 - 2533

Published: Nov. 20, 2022

Maintaining the structure of protein and peptide drugs has become one most important goals scientists in recent decades. Cold thermal denaturation conditions, lyophilization freeze drying, different pH concentrations, ionic strength, environmental agitation, interaction between surface liquid air as well solid, even architectural storage containers are among factors that affect stability these therapeutic biomacromolecules. The use genetic engineering, side-directed mutagenesis, fusion strategies, solvent addition various preservatives, surfactants, additives some solutions to overcome problems. This article will discuss types stress lead instabilities proteins used pharmaceutics including regulatory proteins, antibodies, antibody-drug conjugates, then all methods for fighting stresses be reviewed. New existing analytical detect instabilities, mainly changes their primary higher order structures, briefly summarized.

Language: Английский

Citations

58
Stabilization challenges and aggregation in protein-based therapeutics in the pharmaceutical industry DOI Creative Commons
Mahdie Rahban, Faizan Ahmad, Mieczyslaw A. Piatyszek

et al.

RSC Advances, Journal Year: 2023, Volume and Issue: 13(51), P. 35947 - 35963

Published: Jan. 1, 2023

Protein-based therapeutics have revolutionized the pharmaceutical industry and become vital components in development of future therapeutics. They offer several advantages over traditional small molecule drugs, including high affinity, potency specificity, while demonstrating low toxicity minimal adverse effects. However, manufacturing processes protein-based presents challenges related to protein folding, purification, stability immunogenicity that should be addressed. These proteins, like other biological molecules, are prone chemical physical instabilities. The drugs throughout entire manufacturing, storage delivery process is essential. occurrence structural instability resulting from misfolding, unfolding, modifications, as well aggregation, poses a significant risk efficacy these overshadowing their promising attributes. Gaining insight into alterations caused by aggregation impact on for advancement refinement Hence, this review, we discussed some features during production, formulation stabilization strategies engineering computational methods prevent aggregation.

Language: Английский

Citations

33
Glycosylation shapes the efficacy and safety of diverse protein, gene and cell therapies DOI Creative Commons
Frances Rocamora, Angelo G. Peralta, Seunghyeon Shin

et al.

Biotechnology Advances, Journal Year: 2023, Volume and Issue: 67, P. 108206 - 108206

Published: June 22, 2023

Over recent decades, therapeutic proteins have had widespread success in treating a myriad of diseases. Glycosylation, near universal feature this class drugs, is critical quality attribute that significantly influences the physical properties, safety profile and biological activity proteins. Optimizing protein glycosylation, therefore, offers an important avenue to developing more efficacious therapies. In review, we discuss specific examples how variations glycan structure glycoengineering impacts stability, safety, clinical efficacy protein-based drugs are already market as well those still preclinical development. We also highlight impact glycosylation on next generation biologics such T cell-based cancer therapy gene therapy.

Language: Английский

Citations

23
A Review of Recent Developments in Biopolymer Nano-Based Drug Delivery Systems with Antioxidative Properties: Insights into the Last Five Years DOI Creative Commons
Magdalena Stevanović, Nenad Filipović

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(5), P. 670 - 670

Published: May 16, 2024

In recent years, biopolymer-based nano-drug delivery systems with antioxidative properties have gained significant attention in the field of pharmaceutical research. These offer promising strategies for targeted and controlled drug while also providing antioxidant effects that can mitigate oxidative stress-related diseases. Generally, healthcare landscape is constantly evolving, necessitating continual development innovative therapeutic approaches (DDSs). DDSs play a pivotal role enhancing treatment efficacy, minimizing adverse effects, optimizing patient compliance. Among these, nanotechnology-driven garnered due to their unique properties, such as improved solubility, release, delivery. Nanomaterials, including nanoparticles, nanocapsules, nanotubes, etc., versatile platforms tissue engineering applications. Additionally, hold immense promise, leveraging natural or synthetic biopolymers encapsulate drugs enable release. numerous advantages, biocompatibility, biodegradability, low immunogenicity. The utilization polysaccharides, polynucleotides, proteins, polyesters biopolymer matrices further enhances versatility applicability DDSs. Moreover, substances emerged key players combating diseases, offering protection against cellular damage chronic illnesses. nanoformulations represents burgeoning research area, substantial increase publications years. This review provides comprehensive overview developments within this area over past five It discusses various materials, fabrication techniques, stabilizers, factors influencing degradation, it highlights emerging trends, challenges, prospects rapidly evolving field.

Language: Английский

Citations

11
Enhanced and Prolonged Immunogenicity in Mice of Thermally Stabilized Fatty Acid-Conjugated Vaccine Antigen DOI Creative Commons

Bo Mi Kim,

Yeonho Kim, Hai V. Ngo

et al.

Vaccines, Journal Year: 2025, Volume and Issue: 13(2), P. 168 - 168

Published: Feb. 10, 2025

Background/Objectives: Influenza vaccines require good thermal stability without the need for refrigerator storage. Although fatty acid-conjugated hemagglutinin (Heg) vaccine antigen provides in both solid and liquid states, its therapeutic effectiveness must be validated vivo. This study aimed to investigate immunogenicity of thermally stabilized Heg-oleic acid conjugate (HOC) compare it with native Heg as a reference. Method: To evaluate HOC immunogenicity, an enzyme-linked immunosorbent assay was used measure inhibition (HI) titers, serum IgG antibody titers (IgG1, IgG2a), cytokine secretion levels (IFN-γ, IL-4) BALB/c mice after intramuscular (IM) injection. Results: Thermally induced higher more sustained IgG1 IgG2a responses than antigen. is typically associated Th2 response, whereas Th1 response. appeared enhance responses, inducing balanced immune Moreover, antigens stimulate broader suggesting stronger longer-lasting memory. The IFN-γ (2.8-fold) IL-4 (6-fold) were significantly increased HOC-immunized group compared group. IFN-γ, that activates demonstrated enhanced ability induce IL-4, promotes indicated also strongly crucial maintaining their structural integrity, enabling continuous exposure stable denaturation. allows cells recognize efficiently form long-term Conclusions: processing efficiency antigen-presenting (APCs) stimulated responses. could provide improved storage but immunogenic efficacy antigen, supporting potential further applications.

Language: Английский

Citations

1