(446f) Direct Observation of the Formation of Dynamic Clusters in Concentrated Monoclonal Antibody Solutions

The development of human therapeutics based on monoclonal antibody (mAb) and related products have evolved rapidly with almost exponential growth in market value. They have found wide application in treating cancer, chronic inflammatory diseases, transplantation, infectious diseases and cardiovascular disease because drugs based on antibodies generally have very high selectivity, low side effects, good reproducibility, and a high success ratio. The importance of mAb based biopharmaceuticals motivates fundamental research into problems related to their manufacture and clinic applications. One industrially important challenge is to control the viscosity of concentrated mAb protein solutions.  A high viscosity hinders the large-scale production, purification, storage and delivery of these drugs. In particular, a viscosity exceeding ~50 mPa•S -s prevents delivering drugs via subcutaneous (SC) injection. This can be easily exceed at the high, protein concentrations, in the range 100~200 mg/ml, that  are required for effective syringe injection.

This anomalous viscosity effect is hypothesized to arise from the formation of dynamic clusters. Here we report the direct observation of these dynamic clusters. mAb cluster size and morphology are estimated by combining neutron spin echo, small angle neutron/x-ray scattering and computer simulations. The dynamic cluster formation is shown to be controllable by the added salt concentration. Cluster formation leads to a dramatic increase in the solution viscosity, conclusively proving the hypothesis.  Our results can aid in the development of mAb formulations with desired physical properties.