G-CSF Analog Compositions and Methods

Technology #9044

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Demonstrates a plot of one of the methods of the invention, demonstrating cellular proliferation and binding activity of several G-CSF analogs in relation to wild-type G-CSF.
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Inventors
Professor Casim Sarkar
Department of Biomedical Engineering, University of Minnesota
External Link (sarkarlab.umn.edu)
Professor Douglas Lauffenburger
Department of Biological Engineering, MIT
External Link (web.mit.edu)
Professor Bruce Tidor
Department of Biological Engineering, MIT
External Link (groups.csail.mit.edu)
David Brems
Amgen
Managed By
Jon Gilbert
MIT Technology Licensing Officer
Patent Protection

Methods of Using G-CSF Analog Compositions

US Patent 7,371,370
Publications
Rational cytokine design for increased lifetime and enhanced potency using pH-activated ‘histidine switching
Nature Biotechnology, Aug. 5, 2002, p. 908-913
Cell-level pharmacokinetic model of granulocyte colony-stimulating factor: implications for ligand lifetime and potency in vivo
Molecular Pharmacology, Jan. 2003, p. 147-158
“Querying quantitative logic models (Q2LM) to study intracellular signaling networks and cell-cytokine interactions
Biotechnology Journal, Mar. 2002, p. 374-386

Applications

Granulocyte colony-stimulating factor (G-CSF) analogs can be used in vivo to regulate the hematopoietic and immune systems, and to treat any condition characterized by a reduced hematopoietic or immune function, including a variety of hematopoietic, neurological, and reproduction related conditions. They can also be used in vitro to culture and mobilize hematopoietic cells, such as bone marrow cells or peripheral blood progenitor cells.

Problem

G-CSF produces its effects on the hematopoietic and immune systems by binding to CSF receptors (CSFRs) on the membranes of hematopoietic cells. This triggers a downstream signaling cascade that enhances hematopoietic cell mobility and differentiation. However, after experiencing a prolonged exposure to wild type G-CSF and its currently available analogs, hematopoietic cells will begin to internalize and degrade G-CSF-bound CSFRs. As a result, G-CSF stimulation loses efficacy over time. New G-CSF analogs that incorporate structural changes to reduce this degradation, but that retain binding efficacy to G-CSFRs, would be a substantial improvement to current G-CSF analogs available in the industry.

Technology

Several single amino acid mutations have been shown by the inventors to lead to the reduced degradation of G-CSFs bound to CSFRs. In particular, histidine substitutions at several amino acid sites can lead to electrostatic changes in the binding domain of the G-CSF analogs, which alters its binding affinity to CSFRs inside the cell and promotes recycling of internalized analogs, thus attenuating the degradation processes that traditionally occur after prolonged stimulation. Because the modified G-CSF analogs are not as easily degraded, they can be administered less frequently than currently existing G-CSF analogs. This invention incorporates not only the G-CSF analogs themselves, but also the nucleic acid sequences that encode these new G-CSF analogs, methods for G-CSF production in prokaryotic and eukaryotic host cells, and the compositions of therapeutic solutions of G-CSF along with the necessary buffers and preservatives for injection and for topical, nasal, and oral applications.

Advantages

  • Simple single amino acid changes to current G-CSF analogs
  • Reduced degradation of G-CSF molecules bound to CSFRs
  • Retention of CSFR activation capability
  • Less frequent administration of G-CSF necessary to produce same results