(T1030-01-05) Development of Modality-Agnostic Strategies for High Concentration Biologic Candidate Selection

Purpose: The strategies to select a monoclonal antibody (mAb) candidate from early discovery are widely available. Many of them relied on the “platform” approach to streamline the candidate selection process. However, this platform approach is not necessarily applicable to non-mAbs modalities. With the increased number of non-mAb biologics in development, there is an urgent need for efficient and modality-agnostic strategies for candidate selection.

Methods: Using in-house molecules as candidates, each candidate underwent biophysical assessment and temperature stress at concentrations as low as 10 mg/mL in three platform buffers. Biophysical methods evaluated structural stability and colloidal stability, where nano differential scanning fluorimetry was used to discover melting and onset temperatures, and dynamic light scattering was used to measure the diffusion interaction constant. Low concentration temperature stability was implemented by incubating molecules at accelerated and stressed temperatures to understand the degradation pathways. With the completion of biophysical and low concentration stability assessment, an optimal buffer formulation was selected for each molecule to proceed in a high concentration formulation screening, where candidates were concentrated to 150 mg/mL followed by structural stability testing, and stability testing at storage, accelerated, and stressed temperatures.

Results: Our strategies identify late stage -ready formulations for molecules to be concentrated up to 150 mg/mL at candidate selection stage where materials and development time are limited. These strategies are applicable to multi-modalities including minibody, fusion protein, and typical mAb. Additionally, with sufficient historical data, statistical based approaches can be applied to define risk levels identified when utilizing this candidate selection roadmap.

Conclusion: The strategies employed throughout effectively screened and identified candidates and optimal formulations for high concentration development across different modalities. Ultimately, this comprehensive approach generates a data package that can be highly impactful in a collaborative environment with both early discovery and development groups under the accelerated timeline. 


Figure 1. Pictorial depiction of the 3-stage strategy employed for candidate comparison read from left to right. Stage 1 involves processing the material by dialysis into 3 buffers followed by concentration up to 20 mg/mL. Stage 2 commences with the start of biophysical assessments (structural assessment and colloidal stability) and low concentration thermal stability at 10 mg/mL. Based on data generated in Stage 2, the optimal buffer is selected, and high concentration assessment begins, including concentration up to 150 mg/mL, thermal stability, and viscosity measurements.


Table 1. Rate of change per month at 25°C of high molecular weight species, low molecular weight species, acidic variants, and basic variants for four pipeline molecules. Upper and lower 95% confidence intervals included.