The search for novel proline analogs for viscosity reduction and stabilization of highly concentrated monoclonal antibody solutions

Prašnikar, Monika (author), Proj, Matic (author), Bjelošević Žiberna, Maja (author), Lebar, Blaž (author), Knez, Benjamin (author), Osel, Nika (author), Roškar, Robert (author), Gobec, Stanislav (author), Grabnar, Iztok (author), Žula, Aleš (author), Ahlin Grabnar, Pegi (author)

Administration of monoclonal antibodies (mAbs) is currently focused on subcutaneous injection associated with increased patient adherence and reduced treatment cost, leading to sustainable healthcare. The main bottleneck is low volume that can be injected, requiring highly concentrated mAb solutions. The latter results in increased solution viscosity with pronounced mAb aggregation propensity because of intensive protein-protein interactions. Small molecule excipients have been proposed to restrict the protein-protein interactions, contributing to reduced viscosity. The aim of the study was to discover novel compounds that reduce the viscosity of highly concentrated mAb solution. First, the chemical space of proline analogs was explored and 35 compounds were determined. Viscosity measurements revealed that 18 proline analogs reduced the mAb solution viscosity similar to or more than proline. The compounds forming both electrostatic and hydrophobic interactions with mAb reduced the viscosity of the formulation more efficiently without detrimentally effecting mAb physical stability. A correlation between the level of interaction and viscosity-reducing effect was confirmed with molecular dynamic simulations. Structure rigidity of the compounds and aromaticity contributed to their viscosity-reducing effect, dependent on molecule size. The study results highlight the novel proline analogs as an effective approach in viscosity reduction in development of biopharmaceuticals for subcutaneous administration.

• Language: English
• Keywords: proline analogs, monoclonal antibodies, subcutaneous administration, viscosity reducers, high concentration
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 13 str.
• Numbering: Vol. 655, art. 124055
• PID: 20.500.12556/RUL-155599
• UDC: 615.4:54
• ISSN on article: 0378-5173
• DOI: 10.1016/j.ijpharm.2024.124055
• COBISS.SI-ID: 191471875
• Publication date in RUL: 08.04.2024

Record is a part of a journal

• Title: International journal of pharmaceutics
• Shortened title: Int. j. pharm.
• Publisher: Elsevier/North-Holland
• ISSN: 0378-5173
• COBISS.SI-ID: 3087631

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: farmacevtska kemija, prolinovi analogi, monoklonska protitelesa, subkutana aplikacija, sredstva za zmanjševanje viskoznosti, visoka koncentracija

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P1-0189
• Name: Farmacevtska tehnologija: od dostavnih sistemov učinkovin do terapijskih izidov zdravil pri otrocih in starostnikih

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: L1-3160
• Name: Razvoj visokokoncentriranih proteinskih formulacij in vrednotenje kinetike absorpcije po subkutani aplikaciji