Enhancing viscosity control in antibody formulations: A framework for the biophysical screening of mutations targeting solvent-accessible hydrophobic and electrostatic patches

Abstract The formulation of high-concentration monoclonal antibody (mAb) solutions in low dose volumes for autoinjector devices poses challenges in manufacturability and patient administration due to elevated solution viscosity. In the current study, we present a systematic experimental framework for the computational screening of molecular descriptors to guide the design of mutants with modified viscosity profiles accompanied by experimental evaluation. Our observations using a model anti-IL8 antibody reveal that the reduction in viscosity is influenced by the location of hydrophobic interactions, while targeting positively charged patches in mAb1 leads to the most significant viscosity increase compared to the wild-type mAb. We conclude that existing in silico predictions of physicochemical properties exhibit poor correlation with experimental parameters for antibodies with suboptimal developability characteristics, emphasizing the necessity for comprehensive case-by-case evaluations of mAbs. This approach aids in the rational design of mAbs with tailored solution viscosities, ensuring improved manufacturability and patient convenience in self-administration scenarios.