Descrizione del progetto
Una soluzione inedita per lo sviluppo di anticorpi monoclonali ad alta concentrazione
Il problema della solubilità delle proteine rappresenta una sfida fondamentale nello sviluppo di formulazioni ad alta concentrazione proteica di terapie con anticorpi monoclonali (mAb). Il progetto SWIRL, finanziato dall’UE, affronta questo ostacolo sfruttando l’acido ribonucleico (RNA) quale partner di interazione biologica delle proteine. I ligandi di RNA corti e debolmente interagenti (SWIRL, Short, Weakly Interacting RNA Ligands) aumenteranno la solubilità delle proteine bersaglio, prevenendo l’aggregazione indesiderata tramite interazioni specifiche e l’alterazione della struttura del solvente. Un vantaggio determinate degli SWIRL è offerto dalla loro non-immunogenicità e biodegradabilità. L’obiettivo del progetto è sviluppare e commercializzare un pacchetto software computazionale per la progettazione di SWIRL che migliorino la solubilità di terapie mAb soggette ad aggregazione in un contesto biofarmaceutico.
Obiettivo
Usage of therapeutic monoclonal antibodies (mAbs) has over the past 20 years become one of the most powerful pharmacological strategies in the treatment of various types of cancer, cardiovascular diseases and autoimmune disorders. Importantly, a central challenge in developing the required high protein concentration formulations of mAb therapeutics is the issue of protein solubility. The current approaches for addressing this challenge typically involve using different osmolyte excipients such as salts, carbohydrates, amino acids or surfactants, but they suffer from various problems including insufficient activity, low specificity, allergenic reactivity and others. Clearly, there exists an unmet need for novel strategies to increase the solubility of mAbs in pharmaceutical formulations in an efficient, cost-effective, target-specific manner. We propose to address this challenge by exploiting one of the central biological interaction partners of proteins, the RNA molecules. Specifically, we will: 1) bring to a product stage a computational software suite for designing short, weakly interacting RNA ligands (SWIRLs) that improve the solubility of aggregation-prone mAb therapeutics in a sequence- specific manner, and 2) commercialize the software for usage in a biopharmaceutical context. The designed SWIRLs increase the solubility of target proteins and shield them from unwanted aggregation through weak, specific interactions and a simultaneous alteration of solvent structure. Moreover, a major advantage of using short, standard unmodified RNAs is that they are non-immunogenic and are degradable in the blood, which makes them a unique material for formulation development. Importantly, the sequence-specific design of SWIRLs for a particular target protein will be based on fundamental physicochemical principles of RNA-protein interactions, recently elucidated by us in the context of our ERC Starting Independent grant project.
Campo scientifico
- natural sciencescomputer and information sciencessoftware
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesclinical medicinecardiologycardiovascular diseases
- natural sciencesbiological sciencesbiological behavioural sciencesethologybiological interactions
- natural sciencesbiological sciencesgeneticsRNA
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-POC - Proof of Concept GrantIstituzione ospitante
1010 Wien
Austria