High potency alone does not make a viable biologic drug. Many promising candidates fail in development due to poor manufacturability, instability, aggregation, or chemical liabilities. Integrating developability assessment from the earliest stages of discovery is essential.
Pillar 1: Manufacturability and Expression
The candidate must be producible at viable commercial titers in standard expression systems like CHO cells. Target titers of >1 g/L are the benchmark for commercial feasibility.
Pillar 2: Stability (Thermodynamic and Colloidal)
Thermodynamic stability is assessed via melting temperature (Tm) using differential scanning calorimetry (DSC) or differential scanning fluorimetry (DSF). Colloidal stability (the propensity for protein-protein interactions in solution) is measured by dynamic light scattering (DLS) or self-interaction nanoparticle spectroscopy (SINS).
Pillar 3: High Solubility and Low Aggregation Propensity
Surface hydrophobicity analysis identifies patches that drive aggregation. Size-exclusion chromatography (SEC) testing quantifies the fraction of monomer vs. aggregate species. High monomer percentage at target formulation concentrations is essential.
Pillar 4: Chemical Stability and Lack of Post-Translational “Hotspots”
Sequence liabilities that drive chemical degradation must be identified and eliminated early:
- Deamidation: Asparagine residues, particularly at N-G and N-S motifs
- Isomerization: Aspartate residues converting to isoaspartate
- Oxidation: Methionine and tryptophan residues
- Unpaired cysteines: Leading to disulfide scrambling and aggregation
- Unwanted glycosylation sites: N-X-S/T sequons in binding regions
Conclusion: Integrating Developability from Day One
The most efficient path to a viable biologic is to assess developability in parallel with affinity and specificity screening, not as a late-stage gate. Surface display platforms enable simultaneous selection for function and expression, making early developability assessment practical at library scale.