Introduction -- Targeting glucocerebrosidase to macrophages for effective treatment of patients with Gaucher disease: setting the paradigm of a "fit for purpose" approach to enzyme replacement therapy -- Challenges of Enzyme Replacement Therapy: Poor tissue distribution in lysosomal diseases using Pompe disease as a model -- Muscle targeting -- Blood-Brain Barrier Targeting of Therapeutic Lysosomal Enzymes -- Novel Methods for Addressing Immunogenicity in Therapeutic Enzymes -- Structure of monoclonal antibodies -- Prediction of aggregation in vivo by studies of therapeutic proteins in human plasma -- Effect of Hydrolytic Degradation on the In Vivo Properties of Monoclonal Antibodies -- Oxidation of proteins in the in-vivo environment: what we know; what we need to study and potential mitigation strategies -- Molecular assessment: balancing affinity, PK and manufacturability -- Perspectives on engineering biobetter therapeutic proteins with greater stability in inflammatory environments -- Antibody-like molecules designed for superior targeting and pharmacokinetics -- Alternative protein scaffolds as novel biotherapeutics -- Current strategies for pharmacokinetic optimization -- Biosimilar and Biobetter Scenarios for the US and Europe: What Should We Expect? -- Regulatory considerations for approval of biobetter products.