Antibody therapeutics are the most rapidly growing class of human therapeutics today. Because of their specificity and pharmacological properties, antibody-based therapeutics are showing potential for being more effective and safer than existing small molecules in the treatment of many diseases. The BioLOGIC approach (Figure 1) assists with the development of antibody-based therapeutics through the use of computational modeling and library design, construction of high-fidelity libraries, and high-throughput selection.
Computational modeling and library design: A DNA library contains a collection of closely related DNA constructs coding for variations of a protein to be engineered—an antibody in this example. Using advanced predictive software, the approach can use antibody-antigen crystal structures or homology models to predict mutations that would most likely enhance the desired property of the antibody, typically affinity. This technology enables a protein engineer to rationally design a library that would most likely contain a desired mutant.
Construction of a high-fidelity library: High-capacity library synthesis technology manufactures up to 1012 unique sequences simultaneously with position-defined diversity. Error filtration using a MutS repair system binds and removes errors of mismatched dsDNA, thus maximizing the effective library size by creating extremely high-fidelity libraries. The high percentage of high-value clones (e.g., correct clones designed for optimal functionality) saves time and the cost associated with subsequent screening.(Figure 2)
High-throughput selection: The Biotin Mediated Display (BMD) system, a form of yeast display, can screen libraries up to 108 clones for mutants that bind to a disease marker or antigen. In addition to other classes of proteins, BMD is capable of displaying an intact, full-length antibody instead of antibody fragment, saving time and guaranteeing the binding fidelity of the final full-length form. BMD enables the quick transition from surface displayed protein to a soluble form, cutting assay and characterization times.