| The medical importance of monoclonal antibody therapeutics continues to grow with over 300 such therapeutics under development and more than 25 already approved. Most such therapies are delivered systemically through intravenous, intramuscular, or subcutaneous administration with repeat bolus dosing. Indications in tumor regression, osteoarthritis, or inflammation would benefit from the availability of sustained local delivery systems. Despite their appeal, sustained local delivery systems for antibodies are not readily available. Three factors are thought to contribute to the scarcity of such products: therapeutic protein instability, protein incompatibility with delivery matrix processing or degradation products, and segregation of protein and matrix development.;A multi-step approach is described in which a therapeutic antibody, a silk delivery matrix, and silk-antibody interactions are characterized in parallel. Initially, the solution behavior of a model antibody was evaluated. Low pH insolubility, structural destabilization between pH 6.0 and 7.0, deamidation, and methionine oxidation were identified as modes of instability. Second, a novel silk material format, the antibody-loaded lyogel, was produced by lyophilization of sonication induced silk hydrogels. The lyophilization process imparted significant sustained release properties on the lyogel compared to the parent hydrogel material. Third, a complex mechanism describing antibody release from silk lyogels was defined. The strongest parameter governing antibody release was hydration behavior of the silk lyogel matrix, which was controlled by silk matrix density. Secondary ionic repulsions also played a critical role in antibody recovery and release. While difficult to fully characterize, delivery systems defined by multi-component release mechanisms are desirable because they offer many control points for fine tuning release properties. Finally, characterization of released antibody confirmed a favorable stability profile. No significant changes in physical stability or biological function were observed. Interaction with the silk matrix was found to induce antibody methionine oxidation.;The parallel development approach helped identify effective strategies for antibody stability and release optimization. The improved mechanistic understanding of silk-antibody interactions lead to the creation of a polysorbate loaded lyogel with improved antibody recovery and a methionine loaded lyogel which prevented antibody oxidation. |
