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

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

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.

• Jezik: Angleški jezik
• Ključne besede: proline analogs, monoclonal antibodies, subcutaneous administration, viscosity reducers, high concentration
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: 13 str.
• Številčenje: Vol. 655, art. 124055
• PID: 20.500.12556/RUL-155599
• UDK: 615.4:54
• ISSN pri članku: 0378-5173
• DOI: 10.1016/j.ijpharm.2024.124055
• COBISS.SI-ID: 191471875
• Datum objave v RUL: 08.04.2024

Gradivo je del revije

• Naslov: International journal of pharmaceutics
• Skrajšan naslov: Int. j. pharm.
• Založnik: Elsevier/North-Holland
• ISSN: 0378-5173
• COBISS.SI-ID: 3087631

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: farmacevtska kemija, prolinovi analogi, monoklonska protitelesa, subkutana aplikacija, sredstva za zmanjševanje viskoznosti, visoka koncentracija

Projekti

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: P1-0189
• Naslov: Farmacevtska tehnologija: od dostavnih sistemov učinkovin do terapijskih izidov zdravil pri otrocih in starostnikih

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: L1-3160
• Naslov: Razvoj visokokoncentriranih proteinskih formulacij in vrednotenje kinetike absorpcije po subkutani aplikaciji