[Federal Register Volume 65, Number 156 (Friday, August 11, 2000)]
[Notices]
[Pages 49248-49249]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-20370]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


National Cancer Institute (NCI); Rational Design of Hepatocyte 
Growth Factor (HGF) Agonists and Antagonists

    An opportunity for a Cooperative Research and Development Agreement 
(CRADA) is available for collaboration with the NCI intramural 
Structural Biophysics Laboratory 9SBL) to rationally design agonists 
and antagonists to hepatocyte growth factor (HGF). Collaborative 
projects will focus upon cancer and/or areas of infectious diseases of 
high public health significance and high national and international 
priority.
AGENCY: National Cancer Institute, National Institutes of Health, PHS, 
DHHS.

ACTION: Notice of an opportunity for Cooperative Research and 
Development Agreement (CRADA).

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SUMMARY: Pursuant to the Federal Technology Transfer Act of 1986 (FTTA, 
15 U.S.C. 3710; and Executive Order 12591 of April 10, 1987, as amended 
by the National Technology Transfer and Advancement Act of 1995), the 
National Cancer Institute (NCI) of the National Institutes of Health 
(NIH) of the Public Health Service (PHS) of the Department of Health 
and Human Services (DHHS) seeks one Cooperative Research and 
Development Agreement (CRADA) with a pharmaceutical or biotechnology 
company to rationally design agonists and antagonists to hepatocyte 
growth factor (HGF). The CRADA would have an expected duration of one 
(1) to five (5) years. The goals of the CRADA include the rapid 
publication of research results and timely commercialization of 
products, methods of treatment or prevention that may result from the 
research. The CRADA Collaborator will have an option to negotiate the 
terms of an exclusive or non-exclusive commercialization license to 
subject inventions arising under the CRADA and which are the subject of 
the CRADA Research Plan.

ADDRESSES: Proposals and questions about this CRADA opportunity may be 
addressed to Jeffrey W. Thomas, Technology Development and 
Commercialization Branch, National Cancer Institute-Frederick Cancer 
Research and Development Center, Fairview Center, Room 502, Frederick, 
MD 21701 (phone: 301-846-5465; fax: 301-846-6820; e-mail: jeffreyt@ 
mail.nih.gov).
    Scientific inquiries should be submitted to Dr. R. Andrew Byrd, 
Chief, Structural Biophysics Laboratory, National Cancer Institute-
Frederick Cancer Research and Development Center, Bldg. 538, Room 120, 
Frederick, MD 21702-1201 (phone: 301-846-1407; Fax: 301-846-6231; e-
mail rabyrd@ ncifcrf.gov).

EFFECTIVE DATE: Inquiries regarding CRADA proposals and scientific 
matters may be forwarded at any time. Confidential, preliminary CRADA 
proposals, preferably two pages or less, must be submitted to the NCI 
on or before September 11, 2000. Guidelines for preparing final CRADA 
proposals will be communicated shortly thereafter to all respondents 
with whom initial confidential discussions will be have established 
sufficient mutual interest.

SUPPLEMENTARY INFORMATION:

Technology Available

    The Structural Biophysics Laboratory, DBS, NCI is seeking a 
collaborative partner to pursue the rational design of hepatocyte 
growth factor (HGF) agonists and antagonists. HGF is a secreted, 
heparin-binding protein that stimulates mitogenesis, motogenesis, and 
morphogenesis in a wide spectrum of cellular targets including 
epithelial, endothelial, and hematopoietic cells, as well as 
hepatocytes. HGF and its receptor, c-Met, are essential for embryonic 
development, and HGF signaling contributes to tissue repair and organ 
homeostasis throughout adulthood. Inherited activating mutations in c-
Met are associated with renal papillary carcinoma, and ligand-
stimulated pathway activation has been implicated in the growth, 
neovascularization, invasiveness, and metastasis of several other human 
tumors. The restorative, as well as the deleterious potential of this 
pathway make it a promising target for therapeutic intervention against 
several degenerative and neoplastic diseases. The HGF gene encodes 
full-length HGF, and two truncated isoforms (NK1 and NK2) which consist 
of the N-terminal domain (N) linked to the first one (K1) or two 
(K1+K2) kringle domains. Both truncated isoforms are motogenic; NK1 
also retains the mitogenic and morphogenic potency of HGF, while NK2 is 
a competitive antagonist of these activities. The primary heparin and 
receptor binding sites of HGF reside in the N and K1 domains, 
respectively. Three dimensional structures of N and NK1 obtained using 
NMR spectroscopy and X-ray crystallography suggest that ligand 
dimerization, augmented by heparin binding, may facilitate receptor 
activation. This information provides the basis for [1] determining the 
solution structure of an NK1-heparin complex; [2] locating K2 in NK2 to 
learn the structural basis for its antagonistic properties; [3] 
identifying receptor binding residues in K1, [4] creating NK1 and NK2 
mutants with altered heparin and receptor binding properties, and [5] 
assessing these proteins as activators or inhibitors of HGF signaling 
using cultured cells and intact animals. Achieving these goals will 
help elucidate the mechanism by which HGF

[[Page 49249]]

and heparin cooperate to bind and activate c-Met, and facilitate the 
development of prototypical reagents that potently modulate HGF 
signaling in vivo.
    The Structural Biophysics Laboratory, DBS, NCI is seeking a 
collaborative partner with experience in HGF molecular biology to 
design and construct cDNAs encoding mutant NK1 and NK2 proteins. The 
SBL will determine the structural basis for the antagonistic properties 
of the HGF domains based on the solution structure. The collaborating 
partner in conjunction with the SBL will identify mutants based on the 
structural data provided by SBL that have the potential to address the 
ideas noted above. The collaborating partner will create the identified 
mutants, perform the initial expression, purification, and biological 
characterization of mutant proteins. In addition the collaborating 
partner will evaluate the mutants to determine the HGF agonist/
antagonist properties in cultured cell lines and mice. The SBL and 
collaborating partner will jointly assess and interpret the data to 
understand the role of HGF in c-Met activation and to develop reagents 
to modulate HGF signaling. Accordingly, DHHS now seeks collaborative 
arrangements for the joint SBL and collaborator discovery research and 
development of rationally designed agonists and antagonists to HGF. For 
collaborations with the commercial sector, a Cooperative Research and 
Development Agreement (CRADA) will be established to provide for 
equitable distribution of intellectual property rights developed under 
the research plan of the CRADA.

NCI and Collaborator Responsibilities

    The role of the National Cancer Institute in this CRADA will 
include, but not be limited to:
    1. Providing intellectual, scientific, and technical expertise and 
experience to the research project.
    2. Providing the Collaborator with NMR solution structure 
information to assist in the design of HGF agonists and antagonists.
    3. Planning research studies and interpreting research results.
    4. Publishing research results.
    The role of the CRADA Collaborator may include, but not be limited 
to:
    1. Providing significant intellectual, scientific, and technical 
expertise or experience to the research project.
    2. Providing essential research materials, such as enzymes or other 
reagents, extracts, compounds, hardware or software.
    3. Planning research studies, preparing and providing mutants and 
interpreting research results.
    4. Providing technical expertise and/or financial support (e.g. 
facilities, personnel and expertise) for CRADA-related research as 
outlined in the CRADA Research Plan.
    5. Publishing research results.
    Selection criteria for choosing the CRADA Collaborator may include, 
but not be limited to:
    1. The ability to collaborate with NCI on research and development 
of this technology involving rational design of HGF agonists and 
antagonists. This ability can be demonstrated through experience, 
expertise, and the ability to contribute intellectually in this or 
related areas.
    2. The demonstration of adequate resources to perform the research, 
development and commercialization of this technology (e.g. facilities, 
personnel and expertise) and accomplish objectives according to an 
appropriate timetable to be outlined in the CRADA Collaborator's 
proposal.
    3. The willingness to commit best effort and demonstrated resources 
to the research, development and commercialization of this technology 
as defined above.
    4. The demonstration of expertise in the commercial development, 
production, marketing and sales of antitumor products.
    5. The willingness to cooperate with the National Cancer Institute 
in the timely publication of research results.
    6. The agreement to be bound by the appropriate DHHS regulations 
relating to human subjects, PHS policies relating to the use and care 
of laboratory animals, and the dissemination of research tools 
according to NIH policy.
    7. The willingness to accept the legal provisions and language of 
the CRADA with only minor modifications, if any. These provisions 
govern the equitable distribution of patent rights to CRADA inventions. 
Generally, the rights of ownership are retained by the organization 
that is the employer of the inventor, with (1) the grant of a license 
for research and other Government purposes to the Government when the 
CRADA Collaborator's employee is the sole inventor, or (2) the grant of 
an option to elect an exclusive or non-exclusive license to the CRADA 
Collaborator when the Government employee is the sole inventor.

    Dated: August 1, 2000.
Kathleen Sybert,
Chief, Technology Development & Commercialization Branch, National 
Cancer Institute, National Institutes of Health.
[FR Doc. 00-20370 Filed 8-10-00; 8:45 am]
BILLING CODE 4140-01-M