Why is monoclonal antibody stability so important?
Monoclonal antibodies (mAbs) are an increasingly important aspect of drug development. As the concentration of protein in therapeutic mAb formulations is becoming rather high, stability is more of an issue. The concentration of mAb can be more than 150 grams per litre, and at such high concentrations, special attention is required to stabilize the protein.
Several different aspects must be considered when assessing the stability of mAbs. The three main areas we focus on are chemical stability; conformational stability, which is the persistence of secondary and tertiary structures; and also colloidal stability, which depends on the interactions of the protein molecules in solution.
All three of these are affected by the propensity of the mAb to reversibly interact with other MAb molecules. Such associations can lead to the formation of larger aggregates, which impacts colloidal stability. It is also linked to conformational stability because, upon unfolding, hydrophobic parts of the protein become exposed and are attracted to their counterparts in neighboring molecules .
A pronounced, interactive and attractive reversible self-interaction may be augmented by an additional conformation, stability or unfolding event. If conformational instability occurs, the protein may unfold. However, if there is a repulsive interaction, aggregation may not necessarily occur even if unfolding occurs. Finally, the reversible self-interaction may also affect the extent of the solubility of the mAb, and even cause an increase in viscosity at high concentrations. This can preclude its development as an injectable formulation.
Our research involves analysis of protein-protein interactions by dynamic light scattering and the determination of the effects of temperature on the diffusion coefficient to understand interface-induced mAb aggregation.