The challenges posed by low solubility, aggregation and high viscosity may impede development of therapeutic monoclonal antibody (mAb) candidates. <i>Biopharmaceutical informatics</i> applies computational methods to discover molecular level origins of these phenomena in antibody solutions. When applied at early stages, such computational studies can help significantly reduce drug development costs and improve rate of translating discoveries into medicines available in the clinic. However, currently, two factors limit computer simulations of mAb candidates: First, crystal structures of the candidates are often unavailable due to difficulties in crystallizing full length mAbs; Second, large size of mAbs requires significant computational resources for all-atom simulations. Two approximations can help: (i) Homology based models of the full length antibodies can substitute for the lack of crystal structures; (ii) Molecular simulations performed on coarse-grain models of antibodies can reduce the computational requirements. We have performed molecular dynamics simulations for four Pfizer proprietary antibodies whose highly concentrated solutions (&gt;100 mg/mL) in a platform formulation show a range of low to high viscosities. These antibodies were coarse-grained using a twelve-bead model. Our simulations indicate that formation of transient but large scale antibody networks driven by molecular crowding and electrostatics impart order to the highly concentrated solutions of antibodies that demonstrate high viscosities. To reveal detailed information on residue-level features of antibody structures that drive formation of such networks, residue based coarse-grained models of antibodies are needed to be built and validated. MARTINI is a residue-based forced field implemented in NAMD. We have built coarse-grained model for a human b12 mAb and performed dynamic simulations. We compare the results with atomistic simulations of the same mAb, discuss benefits, caveats, and suggest improvements. This work will help to standardize coarse-grained models for antibody solutions and lead to improved understanding of inter-molecular interactions in antibody solutions.

<i>Biopharmaceutical informatics: </i>Understanding behavior of highly concentrated antibody solutions at molecular level via coarse-grained modeling and simulations

249th National Meeting (2015)

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Biopharmaceutical informatics: Understanding behavior of highly concentrated antibody solutions at molecular level via coarse-grained modeling and simulations