Improving Therapeutic Properties of Protein Drugs through Alteration of Intracellular Trafficking Pathways

Abstract

Although intracellular trafficking processes can play a central role in the physiological function of a protein, these same processes can also limit the benefit of the protein when it is taken out of its physiological context and used as a protein drug. Therefore, the properties of certain protein drugs may be improved by manipulating their trafficking pathways to suit their therapeutic function. A detailed consideration of the factors that govern how protein traffic is routed among different cellular destinations can be used to ascertain molecular design criteria for engineering a protein drug so as to alter its trafficking pathway in a beneficial manner. In this review, we summarize studies that have applied this approach to achieve the following three improvements in protein drug function: (1) half‐life extension of the Fc fragment of IgG, (2) half‐life extension of granulocyte colony‐stimulating factor, and (3) increase in cellular association of transferrin.

Protein engineering approaches for regulating blood–brain barrier transcytosis

“…In addition to modulating targeting vector binding affinity or avidity, one could also envision regulating vector-receptor trafficking dynamics by engineering binding properties that are responsive to the trafficking environment. For instance, during CMT, acidification is a key step in the vesicle maturation and sorting process [16] (Figure 1), and this pH gradient has been exploited in protein engineering involving FcRn binding, as well as in natural ligands including transferrin [35]. Along these lines, early work has investigated whether or not pH-sensitive binding could be an additional engineering handle for regulating anti-TfR antibody trafficking and increasing trans-BBB transport [36].…”

Transferrin as a model system for method development to study structure, dynamics and interactions of metalloproteins using mass spectrometry

“…leading to the possibility of apo-Tf binding to TfR at neutral pH. Such interactions, if they indeed exist, must be taken into account when engineering advanced therapeutic strategies that utilize intracellular trafficking pathways [23]. This warranted further, more detailed investigation of the non-canonical forms of Tf that would provide more definitive proof of their existence beyond the circumstantial evidence produced in the early work [5, 7].…”

Intracellular Trafficking Considerations in the Development of Natural Ligand-Drug Molecular Conjugates for Cancer

“…A clear understanding of the intracellular trafficking pathway of Tf is therefore crucial to improving its efficacy as a drug delivery vehicle 58. Through in vitro experiments and mathematical modeling, Murphy and coworkers previously demonstrated that the duration of cellular trafficking of monoclonal anti-transferrin receptor antibodies, or its cellular association, is correlated with the effectiveness of the antibody as a drug delivery vehicle 118,124,125.…”