Computational Methods for Optimizing Biologics Formulation

Protein based biologicstherapeutics whose active ingredient is a protein and most commonly a monoclonal antibodymAbmake up a $billion year market that is expected to double in size byA critical component in the safety and efficacy of biologics is the need to maintain the active protein during long term storage and subsequent injection infusionThe selection of excipients and buffers toward this end is termedformulationProper formulation of a protein based drug is essential to stabilize the active protein from unfolding and to block sites on the folded protein that would otherwise pose an aggregation risk due to undesirable protein protein interactionsPPIImportantlyformulation can be done without altering the sequence ofi ere engineeringthe proteinand is thus an independent tool for bringing a biologic therapeutic to marketCurrent approaches to choosing an optimized formulation are either low throughput experiments or crude computational methods that do not take into account the molecular details of excipient protein interactionsTo understand at the level of atomic interactions how excipient buffer combinations modulate protein stability and aggregation requires a new approachwhich if successfully developed can provide mechanistic insight for rational formulationThe established Site Identification by Ligand Competitive SaturationSILCScomputational platform technology mapsat atomic resolutionthe affinity pattern of the completeD surface of a protein for a wide diversity of chemical functional groupsThe functional group affinity pattern can be used to determine excipients that can bind to and stabilize the activefolded conformation of a protein and bind to and block those regions of the protein that may participate in PPIthereby inhibiting aggregationThe broad goal of the proposal is to develop comprehensive and industry ready workflows for screening excipients that could stabilize the protein structure and prevent aggregationNew computational tools and a graphical user interface will be developed to manage and apply the extensive information generated by SILCS excipient screening and PPI analysisThe tools will predict excipient buffer binding locations and potential regions that can participate in PPI across the complete protein surfaceThis information will then be applied to predict excipients that will stabilize the foldedbiologically active state of the protein and block PPI thereby slowing aggregation while simultaneously considering the impact of buffersThe proposed approaches will be thoroughly validated in collaboration with industrial and government partners against established experimental methods on well characterized systemsUpon successful completion of the project new offerings will be added to the existing SILCS software suite that will minimize the time and costs requirements for the formulation of biologics as well as lead to improved formulations thereby improving clinical outcomesThese capabilities will be implemented in the context of industry ready workflows for direct sale to pharmaceutical companies and for use in contract research for the optimized formulation of biologics Project NarrativeBiopharmaceuticalsincluding monoclonal antibodiesrepresent a growing and important area of new therapeutic agent developmentbut the formulation of biopharmaceuticals remains a bottleneckProposed is a rational formulation design technology using computational methods that will allow screening of a large number of excipient buffer combinations that will result in accelerated and improved biopharmaceutical development thereby facilitating bringing these agents to market as well as improving clinical outcomes!