[Federal Register Volume 59, Number 134 (Thursday, July 14, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-17081]


[[Page Unknown]]

[Federal Register: July 14, 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 Biomedical Use of Novel 
Approaches for HIV-1 Vaccine Development.

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

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SUMMARY: The Department of Health and Human Services (DHHS) seeks an 
agreement with a pharmaceutical or biotechnology company to use a novel 
approach for HIV-1 vaccine development. This novel method for 
immunological focusing of protective effector responses uses site-
directed mutagenesis to reduce the antigenicity of immunodominant 
epitopes for the purpose of preventing these epitopes from eliciting an 
immune response. One example of this is the introduction of N-linked 
carbohydrate. These immunodominant decoy epitopes (decotopes) function 
to focus the immune system away from responding to more conserved, 
immunorecessive and potentially more broadly protective domains. Any 
CRADA for the biomedical use of this technology will be considered.

ADDRESSES: Proposals and questions about this opportunity may be 
addressed to Dr. Raphe Kantor, Office of Technology Development, 
National Cancer Institute-Frederick Cancer Research and Development 
Center, PO Box B, Frederick, MD 21702-1201 Telephone (301) 846-5465, 
Facsimile (301) 846-6820.

SUPPLEMENTARY INFORMATION: To speed the research, development and 
commercialization of this technology, the National Cancer Institute at 
the Frederick Cancer Research and Development Center is seeking an 
agreement with a pharmaceutical or biotechnology company in accordance 
with the regulations governing the transfer of Government-developed 
agents for joint research, development, evaluation, and 
commercialization in the area of HIV-1 vaccine development.
    The National Cancer Institute Laboratory of Tumor Cell Biology has 
been working on novel approaches to HIV-1 vaccine development. Epitope-
specific neutralizing antibodies arise early in the course of HIV 
infection and are generally directed towards immunodominant 
determinants in the third hypervariable domain (V3) and gp41 
transmembrane domain of the major envelope glycoprotein gp160. Since 
this domain is one of the more variable and functional immunodominant 
regions of gp120, variants can arise which escape the effects of 
neutralizing antibodies. Antibodies capable of neutralizing a broader 
range of isolates appear at a later time during the course of the 
infection. These more broadly neutralizing antibodies are not a simple 
collection of different V3-specific antibodies, but instead are 
composed mostly of antibodies that have a higher order of conformation 
and interfere with the binding of virus to CD4. To test whether this 
early response to V3 suppresses, delays or inhibits the subsequent 
response to other parts of the molecule, putative N-linked 
glycosylation sites were introduced into the V3 domain of the molecule 
in an effort to mask V3. Guinea pigs were first primed with live 
recombinant vaccinia virus expressing the N-linked glycosylation 
mutant, then boosted with purified recombinant protein. Neutralizing 
titers of antibodies were produced, a proportion of which were directed 
to other epitopes of gp120.
    Background information including reprints and issued patents is 
available from the above-referenced address. Patent applications and 
pertinent information not yet publicly disclosed can be obtained under 
a Confidential Disclosure Agreement.
    The CRADA aims include the rapid publication of research results 
and their timely commercialization. The CRADA partner will have an 
option to negotiate the terms of an exclusive or nonexclusive 
commercialization license to subject inventions arising under the 
CRADA.
    The role of the Laboratory of Tumor Cell Biology, NCI-FCRDC, in 
this CRADA will include but not be limited to:
    1. Providing recombinant reagent which has already been molecularly 
modified by said technology for further basic and clinical 
applications.
    2. Continuing application of the technology to develop the most 
broadly protective immunogen by mapping the immunogenic hierarchy that 
is involved in decoying, attenuating, or suppressing the host immune 
response.
    3. Using a library of primary HIV-1 isolates representing all major 
genotypes to test breath and magnitude of immune response.
    4. Doing in vitro neutralization in primary cell-based assays (i.e. 
CD+4 PBMCs, blood derived monocyte/macrophage, spleenic 
lymphocytes, liver macrophages and colonic epithelium).
    5. Providing large-scale screening in in vitro neutralization using 
T-cell line based assays.
    6. Developing alternative vaccine delivery systems.
    7. Making available facilities and technology to express, analyze 
and purify recombinant HIV-1 gp160 protein, immunize ALACC-approved 
laboratory animals, raise and assay subsequent immunologic responses.
    8. Performing animal safety and efficacy studies in HIV-1 chimp 
model.
    9. Providing candidate immunogen for Phase I HIV-1 efficacy trial 
and immunotherapeutic trial.
    10. Contracting, as needed, support services at NCI-FCRDC such as 
biomedical supercomputing, x-ray crystallography, and synthesis of 
monoclonal antibodies.
    11. Publishing research results.
    The role of the Collaborator will include but not be limited to:
    1. Providing support for ongoing CRADA-related research in the 
development of vaccine candidates:
    (a) Financial support to facilitate scientific goals,
    (b) Technical or post doctoral level support for further design and 
in vitro and in vivo testing of subunit HIV-1 vaccine candidates,
    (c) Financial and logistical support for clinical trials Phase I-
III.
    2. Using the proposed technology in the development of alternative 
delivery systems (i.e DNA, canary pox, BCG, polio, Salmonella, and 
attenuated vectors), and novel antigen presenting strategies.
    3. Providing and implementing plans to independently secure future 
continuing supplies of candidate immunogens to assure continued 
preclinical and clinical development.
    4. Providing plans and supporting clinical development leading to 
FDA approval of candidate immunogens.
    5. Producing, packaging, marketing and distributing successful 
candidate immunogens.
    6. Using the proposed technology for other novel biopharmaceutical 
applications.
    7. Publishing research results.
    Selection criteria for choosing the CRADA partner will include but 
not be limited to:
    1. The ability to collaborate with NCI on further research and 
development of this technology. This ability can be demonstrated 
through experience and expertise in this or related areas of technology 
indicating the ability to contribute intellectually to the ongoing 
research and development.
    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 Collaborator's proposal.
    3. The ability to perform clinical testing or trials, and obtain 
IND, NDA and FDA approval for a new drug, medical device or apparatus, 
diagnostic or therapeutic test, or treatment modality.
    4. The willingness to commit best effort and demonstrated resources 
to the research, development and commercialization of this technology.
    5. The demonstration of expertise in the commercial development, 
production, marketing and sales of products related to this area of 
technology.
    6. The level of financial support the Collaborator will provide for 
CRADA-related Government activities.
    7. The willingness to cooperate with the National Cancer Institute 
in the timely publication of research results.
    8. The agreement to be bound by the appropriate DHHS regulations 
relating to human subjects, and all PHS policies relating to the use 
and care of laboratory animals.
    9. 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 
which is the employer of the inventor, with (1) the grant of a research 
license to the Government when the CRADA collaborator's employee is the 
sole inventor, or (2) the grant of an option to negotiate for an 
exclusive or nonexclusive license to the Collaborator when the 
Government employee is the sole inventor.
    The following is a listing of Dr. Robert Garrity's patent portfolio 
for this technology:
    Application Title: ``Immunological Focusing of Protective Effector 
Responses Using Site-Directed Mutagenesis or Chemical modification to 
Alter a Specific Protein or Peptide Immunogen for Use in Plant, Animal 
and Human Vaccines and Immunotherapies.''
    Inventors: Dr. Robert R. Garrity, Dr. Peter L. Nara, Dr. Jaap 
Goudsmit.

    Dated: June 25, 1994.
Barbara M. McGarey, J.D.,
Deputy Director, Office of Technology Transfer, National Institutes of 
Health.
[FR Doc. 94-17081 Filed 7-13-94; 8:45 am]
BILLING CODE 4140-01-P