Biologics discovery and early development

Understanding and controlling the quality and stability of assay components, their purity and functionality is fundamental to generating robust, repeatable data.

For biologics, it is often the case that the target and the drug molecule are both proteins. Target and drug must be stable and active under assay conditions to avoid unreliable results, repeat screening requirements, and potentially false negatives. Protein aggregation can compromise the quality of screening activities and it is essential to ensure that all batches of the respective proteins are the same.

Biophysical characterization supports the development and optimization of biochemical, biophysical and cell-based assays to ensure their output enables selection of the most promising hits and candidates. 

In biopharmaceutical discovery, the 'hit' molecules, or 'parental' protein drug molecules, are modified or engineered to improve their expression level, stability, potency, bioactivity or safety, or to make the protein more developable. It is important to evaluate the stability of these recombinant proteins after the engineering steps are complete and before candidate selection. This allows informed selection of appropriate constructs and the rapid elimination of unsuitable variants that might be prone to effects such as thermal lability, increased heterogeneity or a propensity to aggregate.

Malvern Panalytical’s systems help answer questions of binding capability and stability using Isothermal Titration Calorimetry, Differential Scanning Calorimetry and Dynamic Light Scattering.

Determining the activity of potential drug candidates typically involves the use of high-throughput techniques such as Surface Plasmon Resonance (SPR) and Enzyme-Linked Immunosorbent Assay (ELISA). Once activity is profiled, it is essential to know if a molecule presents a practical working proposition. Here, Malvern Panalytical’s biophysical characterization techniques help answer essential questions of whether or not the molecule tends to aggregate or fragment and if it has sufficient thermal stability.

Zetasizer systems are long-established in biopharmaceutical development for aggregate determination, while MicroCal PEAQ-DSC delivers detailed information on thermal stability. OMNISEC size exclusion chromatography helps map any fragmentation that may be occurring.

Moving into preformulation development, where small-scale biophysical studies help define the optimal buffer composition and pH conditions needed to help stabilize the protein, a typical stability screen will involve both DSC and DLS.