Systems approach to therapeutics design.

A general methodology is described for improving the therapeutic properties of protein drugs by engineering novel intracellular trafficking pathways. Procedures for cellular trafficking experiments and mathematical modeling of trafficking pathways are presented. Previous work on the engineering of the transferrin trafficking pathway will be used to illustrate how each step of the methodology can be applied.

[1]  J. Tso,et al.  Engineered Human IgG Antibodies with Longer Serum Half-lives in Primates* , 2004, Journal of Biological Chemistry.

[2]  A Ciechanover,et al.  Kinetics of internalization and recycling of transferrin and the transferrin receptor in a human hepatoma cell line. Effect of lysosomotropic agents. , 1983, The Journal of biological chemistry.

[3]  D. Lauffenburger,et al.  Controlling receptor/ligand trafficking: Effects of cellular and molecular properties on endosomal sorting , 1997, Annals of Biomedical Engineering.

[4]  M. Hentze,et al.  Balancing Acts Molecular Control of Mammalian Iron Metabolism , 2004, Cell.

[5]  S. Everse,et al.  The oxalate effect on release of iron from human serum transferrin explained. , 2004, Journal of molecular biology.

[6]  Bruce Tidor,et al.  Computational design of antibody-affinity improvement beyond in vivo maturation , 2007, Nature Biotechnology.

[7]  P. Bjorkman,et al.  Crystal Structure of the Hemochromatosis Protein HFE and Characterization of Its Interaction with Transferrin Receptor , 1998, Cell.

[8]  Bert J Lao,et al.  Inhibition of transferrin iron release increases in vitro drug carrier efficacy. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[9]  D. Lauffenburger,et al.  Integrating cell-level kinetic modeling into the design of engineered protein therapeutics , 2005, Nature Biotechnology.

[10]  Bruce Tidor,et al.  Quantitative methods for developing Fc mutants with extended half-lives. , 2005, Biotechnology and bioengineering.

[11]  P. Yazdi,et al.  Quantitative analysis of protein synthesis inhibition by transferrin-toxin conjugates. , 1994, Cancer research.

[12]  D. Lauffenburger,et al.  Rational cytokine design for increased lifetime and enhanced potency using pH-activated “histidine switching” , 2002, Nature Biotechnology.

[13]  Michael Weaver,et al.  Transferrin Receptor Ligand-Targeted Toxin Conjugate (Tf-CRM107) for Therapy of Malignant Gliomas , 2003, Journal of Neuro-Oncology.