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).

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 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.