Pace Life Sciences Boston, MA’s proprietary ADC characterization screens are powerful predictors of pharmaceutical properties. The screens leverage an understanding of the fundamental chemical and biophysical behavior of conjugates. Conjugation of monoclonal antibodies to linker-payload systems results in a highly heterogeneous mixture of molecules, which vary in the distribution of drug-antibody ratio (DAR) and site of attachment. Furthermore, the site of attachment directly affects the overall charge of the conjugate. This increased heterogeneity in the electrostatic properties of the conjugates affects stability, solubility and viscosity of proteins.
Pace’s proprietary form and formulation screen characterizes properties of ADCs to inform their performance characteristics and to reliably generate stable, well-behaved protein-drug conjugates and formulations. In addition, other techniques are employed to characterize the biophysical performance.
Characterization of Propensity for Self-Association
The propensity for self-association is a critical parameter to assess early in the drug development process, as formation of aggregates is among the more common degradation mechanisms for biological therapeutics. Aggregation can lead to loss of activity of the drug substance and may cause immunogenicity on administration. Appearance of aggregates, reversible or irreversible, is routinely monitored during formulation development. While reversible association is generally less worrisome than irreversible association, high concentration and formulation conditions such as pH and ionic strength can alter the equilibrium toward formation of irreversible aggregates. Early assessment of the propensity to form reversible and irreversible aggregates can significantly contribute to efficient and effective formulation development and enable the development of the appropriate analytical techniques in advance.
Pace assesses the effect of pH and ionic strength on solubility as part of preformulation studies in order to inform the experimental designs for formulation development. The pH solubility profile is an essential tool for successful development and, in combination with the pH stability profile, serves to inform suitable formulation approaches, as well as the expected in vivo performance.
pH Stability Profile
The pH stability profile is used for understanding how the compound behaves in different pH environments and informs formulation development, process development, drug product stability and administration of the molecule. The goal of the pH stability profile is to identify the pH of maximal stability. Pace Life Sciences can develop mechanism-based approaches to stabilize the molecule with knowledge of the degradation pathways at different pH values.
Exposure to different temperatures during storage and the manufacturing process presents a direct liability to the physical stability. Denaturation and aggregation can occur as a resulted of elevated temperatures as well as on freezing or with freeze/thaw. Aside from the obvious logistical need to prevent degradation, instability caused by storage or process conditions can lead to inaccurate interpretation of studies during development. The storage stability, therefore, needs to be established as early as possible.
Stability to Shear
Drug substances are routinely subjected to various mechanical stresses during sample preparation and manufacturing process, and these stresses may induce conformational changes that at the very least may lead to loss of activity, as well as adsorption, aggregation and precipitation. Understanding which stressors cause instability directly affects sample handling, formulation and process development.