Predictive Nature of High-Throughput Assays in ADC Formulation Screening

Area of Science:

• Biophysical Chemistry
• Pharmaceutical Development
• Drug Stability

Background:

• High-throughput screening (HTS) is crucial for early drug development due to limited sample availability.
• Predicting long-term storage stability from HTS data is essential for defining optimal formulation design spaces.
• Antibody-drug conjugates (ADCs) require robust stability assessments for effective therapeutic development.

Purpose of the Study:

• To evaluate the predictive capability of high-throughput biophysical screening methods for ADC formulation stability.
• To compare the rank order of formulations from HTS assays with results from traditional long-term stability studies.
• To determine which biophysical assays best predict colloidal and conformational stability of ADCs.

Main Methods:

• Two ADCs were tested across 16 different formulation conditions.
• High-throughput techniques were used to assess conformational stability (Tm) and colloidal stability (kD, B22, Tagg).
• Samples underwent an 8-week stability study to monitor aggregate formation, with results compared to HTS data.

Main Results:

• High-throughput assays measuring aggregation (Tagg, B22) showed rank orders similar to traditional size exclusion chromatography (SEC) data.
• Conformational stability assays (Tm) demonstrated lower predictability for long-term stability.
• Screening assays successfully identified poorly performing formulation conditions, aligning with desired outcomes.

Conclusions:

• High-throughput assays like Tagg and B22 are valuable for predicting ADC aggregation and colloidal stability.
• Conformational stability measurements (Tm) are less reliable predictors of long-term storage stability.
• HTS biophysical methods effectively identify suboptimal formulations, supporting efficient ADC development.