Sutro’s cell-free expression technology provides a rapid and powerful platform for the discovery and development of next generation antibody-drug conjugates (ADCs). Current ADCs in development have immense promise, but they are limited by the fact that they are structurally heterogeneous populations in which the position and number of conjugated linkers and warheads vary significantly. Such heterogeneity prevents the definition of structure-activity relationships (SARs). Consequently, using traditional ADC technologies prevents researchers from discovering and developing candidates with optimal therapeutic indices and can result in products with unpredictable and sub-optimal pharmacokinetic properties, stability and efficacy.
Sutro can incorporate non-natural amino acids (nnAA) at any site in an antibody structure, thereby allowing for single-species ADCs with site-specific conjugation of linker and warhead. Of vital importance in this process is Sutro’s ability to perform rapid and parallel synthesis of numerous variants taking advantage of a substantial number of different sites, enabling analyses early in discovery to define SARs and locate the best positions for nnAA incorporation based on:
- Protein expression levels
- Efficiency of incorporation of the nnAA
- Linker / warhead conjugation efficiency
- Target binding efficiency
- Cell killing efficiency
- Internalization characteristics
It has been well documented that the cell-killing effects of ADCs are highly dependent on the location of the warhead as well as the drug to antibody ratio. Sutro can control both of these variables with exquisite specificity, resulting in truly optimized product candidates. Sutro has also addressed the challenge of manufacturing nnAA-containing ADCs by engineering additional versions of cell-free extract that achieve high rates of incorporation of nnAAs and by developing chemistries that allow for efficient conjugation of linkers and warheads to antibodies.