[Federal Register Volume 59, Number 100 (Wednesday, May 25, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-12688]
[[Page Unknown]]
[Federal Register: May 25, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Cancer Institute: Opportunity for a Cooperative Research
and Development Agreement (CRADA) for the Identification of
Biomolecules Involved in HIV Entry Into Cells and Metastatic Tumor Cell
Invasion
AGENCY: National Institutes of Health, PHS, DHHS.
ACTION: Notice.
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SUMMARY: The National Cancer Institute (NCI) seeks an agreement with a
pharmaceutical or biotechnology company for the joint research,
development, evaluation and possible commercialization of biomolecules
involved in HIV entry into cells and metastatic tumor cell invasion.
Elucidation of such components will lead to the design of reagents
which will interfere with HIV entry and/or tumor invasion. These
reagents will subsequently be tested on animal models and in eventual
clinical trials for their efficacy as therapeutic agents.
ADDRESSES: Proposals and questions about this opportunity may be
addressed to Mr. M.W. Noel; Office of Technology Development; National
Cancer Institute; National Institutes of Health; Building 31, Room
4A51; Bethesda, MD 20892.
DATES: Responses must be received no later than July 25, 1994.
SUPPLEMENTARY INFORMATION: Specific fusion of biological membranes is a
central requirement for many cellular processes. It involves phenomena
such as intracellular sorting and secretion, cell division,
fertilization, metastasis and viral entry into cells. The research
goals of the Membrane Structure and Function Section of the Laboratory
of Mathematical Biology (LMMB); Division of Cancer Biology; Diagnosis
and Centers (DCBDC); National Cancer Institute (Dr. Robert Blumenthal,
Chief) have in the past years been directed towards an understanding
how viral envelope proteins mediate fusion of membranes. Dr.
Blumenthal's group has developed new methodologies to examine the
fusion activity of viral proteins.
The goal of this CRADA is to identify the biochemical components of
the fusion complex involved in HIV entry into cells and tumor cell
invasion. A photosensitized labeling approach will be employed for the
identification of membrane fusion and cell adhesion molecules which may
play an important role in HIV entry into cells and/or in metastatic
cell invasion. The use of the photosensitized labeling approach may
make it possible to reveal the biological components and proteins on
cell surfaces (membranes) which could not previously be identified in
any other way. Background information (including reprints) is available
from the above-referenced address. Selected peptide components of the
fusion complex will be purified and micro-sequenced in order to proceed
with hybridization cloning of the accessary fusion molecules. Reagents
such as peptides and antibodies will then be generated using
information derived from their cDNA sequences. The reagents will be
screened and tested for their ability to interfere with or block HIV
infection and/or metastatic cell invasion using in vitro assays. Potent
inhibitors thus identified will be further tested on animal models and
in eventual clinical trials for their efficacy as therapeutic agents.
(1) HIV: It has been shown that human CD4 inserted into non-human
cells will not support HIV-1 entry into those cells. Protease-
insensitive components of human cells are needed to overcome the block
in HIV-1 envelope glycoprotein-mediated fusion of non-human cells. The
plan is to identify those putative components using a new technique
called photosensitized labeling. By this methodology, lipophilic aryl
azides are photoactivated in situ by energy transfer from a variety of
chromophores, using visible light. This approach has been successfully
applied to the identification of proteins and lipids involved in
multidrug resistance of tumor cells and the process of invasion of
human erythrocytes by the Malaria parasite. Peptides derived from
specific regions of gp 120 and gp 41 are labeled with fluorescein or
other chromophores and photoactivated during their interaction with
CD4+ membranes containing the radioactive probe [125I]-5-
Iodonaphthalene-1-azide (INA). Since photoactivation occurs by
resonance energy only, membrane components in the vicinity of CD4 will
be labeled by INA. The putative accessory proteins forming fusion
complexes with gp 120 and CD4 will presumably be labeled, identified on
2D gels and isolated. The elucidation of such protease-insensitive
components will lead to the design of reagents which will interfere
with or block HIV entry into cells. These reagents will subsequently be
tested on animal models and in eventual clinical trials for their
efficacy as therapeutic agents against HIV infection.
(2) Metastasis: It has been shown that cytokine-induced
pseudopodial protrusion is a prominent feature of actively motile cells
in vitro and invading tumor cells in vivo. Following protrusion of the
pseudopodia through the basement membrane, it has been postulated that
fusion of adjacent pseudopods occurs. This is following by streaming of
the cytoplasm beneath the basement membranes, migration of the nucleus
and finally, relocation of the cell to the opposite side of the
basement membrane. This process results in migration of the tumor cell
towards the target tissue. The pseudopod fusion process is presumably
mediated by membrane fusion-inducing proteins which are transiently
expressed during cell migration across the basement membrane. For the
identification of such proteins, a similar approach will be used as
that for identification of accessory components in HIV-1 envelope
glycoprotein-mediated membrane fusion: the chromophore will be placed
on one population of cells and the 125INA will be placed on
another population of metastatic cell. Upon their penetration through
basement membranes, the pseudopodia of adjacent cells may fuse with one
another. Fusion of a chromophore-labeled membrane with an 125INA-
bearing membrane will cause energy transfer between the chromophore and
INA generating a measurable signal in the form of radiolabeled proteins
located at the site of fusion. The membrane proteins involved in
metastatic cell fusion and invasion will be identified on 2D gels and
isolated. The elucidation of these proteins will lead to the design of
reagents which will interfere with or block tumor invasion into cells.
These reagents will subsequently be tested on animal models and in
eventual clinical trials for their efficacy as therapeutic agents
against tumor cell invasion.
CRADA aims include the rapid publication of research results and
the timely exploitation of commercial opportunities. The CRADA partner
will enjoy rights of first negotiation for licensing Government rights
to any inventions arising under the agreement and will advance funds
payable upon signing the CRADA to help defray Government expenses for
patenting such inventions and other CRADA-related costs.
The role of the Collaborator will be as follows:
1. The Collaborator will provide technology for the identification
of membrane fusion and cell adhesion molecules. In particular, the
Collaborator should be able to provide technology for the
implementation of photosensitized labeling approach for identification
of membrane fusion and cell adhesion molecules.
2. The Collaborator will be responsible for the purification and
micro-sequencing of selected peptides, enabling NCI to proceed with
hybridization cloning of the accessary fusion molecules.
3. The Collaborator will generate reagents (e.g. peptides and
antibodies) using information derived from their cDNA sequences.
4. The Collaborator will provide technology which will allow the
control and synchronization of migratory and invasive processes of
metastatic cells. This technology will be used to model invasion of
metastatic cells in vivo.
5. The Collaborator will screen and test reagents (e.g. peptides
and antibodies) for their ability to block HIV infection and/or
metastatic cell invasion using in vitro assays.
6. Potent inhibitors of HIV infection and/or metastatic cell
invasion identified by screening will be further tested by the
Collaborator on animal models and in eventual clinical trials for their
efficacy as therapeutic agents.
The role of the Division of Cancer Biology Diagnosis and Centers,
NCI, in this CRADA will be as follows:
1. Provide the Collaborator with techniques, expertise and
facilities to study virus-cell interactions.
2. Provide computer and literature search support for the project.
3. Provide access to sophisticated instrumentation (e.g.
fluorescence spectroscopy and video microscopy (imaging), protein
separation).
4. Characterize physicochemical properties of the biomolecules
involved in the fusion process as well as researching their mechanisms
of biological action.
5. Publish these results and provide the Collaborator all data as
soon as they become available.
The selection criteria on which in Collaborator will be chosen are
as follows:
1. The ability to collaborate with NCI on further research and
development of this technology as demonstrated by experience and
expertise in this or a related area of technology.
2. The demonstration of adequate resources to perform the research,
development and commercialization of this technology (i.e. facilities,
personnel) and accomplish the objectives in a timely manner.
3. The willingness to commit best effort to reach CRADA objectives.
4. The level of financial support the collaborator will provide for
CRADA-related NCI activities.
5. A willingness to cooperate with the National Cancer Institute in
the publication of research results.
6. An agreement to be bound by the DHHS rules involving human
subjects, patent rights and ethical treatment of animals.
7. Provisions for equitable distribution of patent rights to any
invention. Generally, the rights of ownership are retained by the
organization which is the employer of the inventor, with: (1) An
irrevocable, non-exclusive, royalty-free license to the Government
(when a company employee is the sole inventor) or (2) an exclusive or
non-exclusive license to the company on terms that are appropriate
(when the Government employee is the sole inventor).
Dated: May 15, 1994.
Barbara M. McGarey,
Deputy Director, Office of Technology Transfer.
[FR Doc. 94-12688 Filed 5-24-94; 8:45 am]
BILLING CODE 4140-10-P
