Overview for Lead Selection & Optimization
Lead selection and optimization is a critical process in the identification, selection and optimization of molecules that meet predefined requirements and can then be progressed to the next step of development. While biologics lead selection mainly involves the screening of lead biological molecules to select those with desired functional and biophysical characteristics, optimization further helps improve these properties and may be performed through various means including affinity maturation and other techniques. Technologies that can aid in integrating the selection and optimization workflow should help in improving the speed and efficiency of the process.
Fragment-based drug design has become an increasingly popular platform for the identification of lead candidates in drug discovery programs. The detection and characterization of fragment binding events is facilitated by sensitive biophysical technologies capable of detecting low affinity interactions of low molecular weight compounds. Surface plasmon resonance (SPR) has become one of the core technologies used in the identification of these low-affinity fragment compounds. SPR-based biosensors such as the Pioneer FE have the necessary sensitivity and throughput to provide complete fragment screens on libraries of several thousand compounds in just a few weeks per target.
Antibody discovery typically refers to the screening and identification of monoclonal antibodies (mAbs) that target a specific epitope for the diagnosis and treatment of diseases. A common approach to generating monoclonal antibodies involves the fusion of a pre-mitotic cancer cell with a post-mitotic and terminal antibody-expressing B-cell from the spleen. The Octet HTX system provides ample throughput for rapid binding and specificities analysis of multiple clones.
- The Octet HTX system provides ample throughput for rapid binding and specificities analysis of multiple clones
Titer determination on the Octet platform
Titer and protein concentration determination is a critical process in the development of biologics drug molecules. The active protein concentration can be used to determine the potency of the drug molecule. While ELISA and especially HPLC are commonplace techniques for titer and protein concentration determination, techniques that are more robust to cell culture and media are especially desirable as they can be easily adopted in both upstream and downstream processes during the development of the drug molecule.
- A full plate (96 samples) of IgG titer can be analyzed in as little as two minutes
- Sample plate format allows for the use of crude and non-purified samples
- Automation capable Octet HTX and RED384 allow for walkaway high throughput analysis
Kinetic characterization and clone selection
The evaluation of kinetics information of drug candidate molecules by monitoring their binding properties to target molecules is a critical process in lead molecule selection and can aid in the selection of desirable clones. Integrated systems that can generate highly-precise data on molecular binding affinities, specificities, and association/dissociation rate constants and in a high throughput manner are desirable.
- Accurately determine ka, kd, and KD
- Screen up to 96 clones simultaneously in 96 or 384-well plates
- Perform analysis directly in crude samples—no need for sample purification
Off-rate screening on Octet systems
Library screening by ELISA does not enable ranking of antibodies based upon their affinities for an antigen. With the Octet system, clones with high affinities and low off-rates can be rapidly identified and selected for further characterization. Many biotechnology companies utilize the Octet system in automated affinity screening and off-rate screening of positive clones obtained from ELISA-based primary screens.
Resources of Lead Selection & Optimization
Application Note Enhancing Efficiency and Economics in Process Development and Manufacturing of Biotherapeutics
Application Note Fragment Based Drug Discovery on Pioneer Systems Using Next Generation SPR Analysis
Fragment-based drug design (FBDD) has become an increasingly popular platform for the identification of lead candidates in drug discovery programs.Read more