Technology ID
E-331-2002-0

Activation of Recombinant Diphtheria Toxin Fusion Proteins by Specific Proteases Highly Expressed on the Surface of Tumor Cells

Linked ID
TAB-875
Inventors
Jennifer Avallone (NIDCR)
Manuel Osorio (NIDCR)
Shihui Liu (NIDCR)
Stephen Leppla (NIDCR)
Thomas Bugge (NIDCR)
Lead Inventors
Shihui Liu (NIDCR)
Co-Inventors
Jennifer Avallone (NIDCR)
Manuel Osorio (NIDCR)
Stephen Leppla (NIDCR)
Thomas Bugge (NIDCR)
Applications
Therapeutics
Therapeutic Areas
Oncology
ICs
NIDCR
This invention relates to diphtheria toxin fusion proteins comprising a diphtheria toxin (DT) cell-killing component and a cell-binding component such as granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 2 (IL-2), or epidermal growth factor (EGF). Receptors for the latter three materials are present on many types of cancer cells; therefore, these fusion proteins bind preferentially to these cancer cells. A key feature is that these toxins are altered so as to require activation by a cell-surface protease that is overexpressed on many types of cancers. Examples of such proteases include matrix metalloproteinases and urokinase plasminogen activator. Consequently, these novel cytotoxins kill tumors expressing receptors for either GM-CSF, IL-2, or EGF along with the cell-surface protease. Because killing requires the presence of both a receptor and a cancer-cell enriched protease, and few normal tissues contain both, there is less toxicity to normal cells. Thus, a larger amount of the agent may be used for cancer therapy without inducing side effects. In other words, these cytotoxins have a higher therapeutic index than toxins that are targeted to cells using a single strategy. {RefNo is 875 }

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