[Federal Register Volume 64, Number 86 (Wednesday, May 5, 1999)]
[Notices]
[Page 24165]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-11204]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Invention; Availability for Licensing; 
``Receptor-Mediated Delivery of Third-Party Proteins and Peptides to 
the Cytosol of Mammalian Cells''

AGENCY: National Institutes of Health, Public Health Service, DHHS.

ACTION: Notice.

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SUMMARY: The invention listed below is owned by or controlled by an 
agency of the U.S. Government and is available for licensing in the 
U.S. in accordance with 35 U.S.C. 207 to achieve expeditious 
commercialization of results of federally funded research and 
development.

ADDRESSES: Licensing information and copies of U.S. patents and patent 
applications referenced below may be obtained by contacting J. R. 
Dixon, Ph.D., at the Office of Technology Transfer, National Institutes 
of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 
20852-3804 (telephone 301/496-7056 ext 206; fax 301/402-0220; E-Mail: 
[email protected]). A signed Confidential Disclosure Agreement is required 
to receive a copy of any patent application.

SUPPLEMENTARY INFORMATION: Invention Title: ``Recombinant Chimeric 
Proteins Deliverable Across Cellular Membranes into Cytosol of Target 
Cells''.

    Inventors; Drs. Ira H. Pastan (NCI), Trevor Prior (NCI), Waldemar 
Y. Debinski (NCI), Clay Siegall (NCI).
    DHHS Ref. No. E-020-91/0 [= USP SN: 5,328,984 (= 07/663,455)--Filed 
March 4, 1991].
    The following patent applications and patents are also available, 
to the extent necessary to practice the technology disclosed in the 
U.S.P. SN: 5,328,984, for licensing from the National Institutes of 
Health's Office of Technology Transfer:
    1. 08/683,621, entitled: ``Hybrid Molecules Having Translocation 
Region and Cell-Binding Region'', inventor: John R. Murphy, Filed: July 
17, 1996. [E-998-98/7]
    2. 5,668,255 [= 08/102,387], entitled: ``Hybrid Molecules Having 
Translocation Region and Cell-Binding Region'', inventor: John R. 
Murphy, Filed: August 4, 1993. [E-998-98/6]
    3. 07/722,484, entitled: ``Hybrid Molecules Having Translocation 
Region and Cell-Binding Region'', inventor: John R. Murphy, Filed: June 
26, 1991. [E-998-98/5]
    4. 07/538,276, entitled: ``Hybrid Molecules Having Translocation 
Region and Cell-Binding Region'', inventor: John R. Murphy, Filed: June 
14, 1990. [E-998-98/4]
    5. 07/456,095, entitled: ``Hybrid Molecules Having Translocation 
Region and Cell-Binding Region'', inventor: John R. Murphy, Filed: 
December 22, 1998. [E-998-98/3]
    6. 06/742,554, entitled: ``Hybrid Protein and Fused Gene Encoding 
Same'', inventor: John R. Murphy, Filed June 7, 1985. [E-998-98/2]
    7. 06/726,808, entitled: ``Hybrid Protein and Fused Gene Encoding 
Same'', inventor: John R. Murphy, Filed: April 25, 1985. [E-998-98/1]
    8. 06/618,199, entitled: ``Hybrid Protein and Fused Gene Encoding 
Same'', inventor: John R. Murphy, Filed: June 7, 1984. [E-998-98/0].

Background

    Protein toxins have several distinctive properties that allow them 
to facilitate the delivery of third-party proteins to the cell cytosol. 
First, they are modular in nature and possess separate domains that 
function independently to perform distinct functions. By domain 
swapping, toxins can be converted into delivery agents. Toxins enter 
cells by receptor-mediated endocytosis, avoid degradation, and 
translocate to the cell cytosol where they are cytotoxic. By disabling 
the toxin's cytotoxicity domain, it is possible to replicate this 
delivery pathway without causing damage to the cell. Further, by 
altering toxin-expressing vectors to include cDNAs encoding non-toxin 
related proteins and peptides, it is possible to mediate delivery of 
third-party proteins from the cell exterior to the cytosol. Thus, 
functionally active proteins can be joined to the toxin translocation 
module and the resulting chimeric protein developed into a delivery 
vehicle. Further the toxins' binding domain can be replaced with 
receptor-binding ligands of choice. By combining domains of different 
origins, various therapeutic proteins can be generated. Toxin-mediated 
delivery to the cytosol can be used for: enzyme replacement (to 
complement a genetic defect), peptide delivery for the generation of 
cytotoxic lymphocytes, delivery of anti-viral peptides, agonist of 
antagonist peptides of signaling pathways, etc.

Invention

    This invention provides a method of making a hybrid foreign protein 
that can be delivered into the cytosol of the target cells across the 
cellular membranes. Further, the present invention provides a suitable 
vector containing a nucleotide sequence that encodes a hybrid protein.
    The advantages of the invention are achieved by (1) providing a 
recombinant molecule possessing at least a recognition element, a 
translocation function, and one or more recombinant sites for inserting 
foreign proteins or polypeptides, and (2) making a recombinant chimeric 
protein translocatable across cellular membranes into the cytosol of 
target cells, said chimeric protein having at least one segment which 
is a functionally active foreign protein desired to be introduced de 
novo into cytosol of target cells, a recognition element that directs 
the hybrid protein to the target cells, and an additional segment 
having at least a translocation function which internalizes the protein 
and delivers the foreign protein into the cytosol of the target cells. 
In the case of Pseudomonas Exotoxin (``PE''), the recombinant sites 
could be located in either or both of domains Ib or III, but not in 
domain II. These chimeric proteins can be used for cytotoxic, 
diagnostic, or therapeutic purposes, such as for compensating the 
deficiency or defect of an enzyme or a protein which may be causative 
of a disease or an abnormality. The above mentioned invention is 
available, including any available foreign intellectual property 
rights, for licensing on an exclusive or non-exclusive basis.

    Dated: April 28, 1999.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer.
[FR Doc. 99-11204 Filed 5-4-99; 8:45 am]
BILLING CODE 4140-01-M