[Federal Register Volume 59, Number 157 (Tuesday, August 16, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-19943]


[[Page Unknown]]

[Federal Register: August 16, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

National Cancer Institute; Opportunity for a Cooperative Research 
Agreement (CRADA) for the Scientific and Commercial Development of 
Monoclonal Antibodies to a Tumor-Specific Growth Factor for the 
Diagnosis and Prognosis of Premalignant Lesions and Cancer

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

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SUMMARY: The National Cancer Institute (NCI) seeks a pharmaceutical or 
biotechnology company that can effectively pursue the scientific and 
commercial generation and development of a panel of monoclonal 
antibodies against an epidermal growth factor (EGF)-related peptide, 
cripto-1 (CR-1). The project is of scientific importance because CR-1 
is a protein that exhibits structural homology to the EGF/transforming 
growth factor  (TGF) gene family peptides. As such, 
CR-1 might function as a growth factor or growth inhibitor. Therefore, 
CR-1 may be important as an autocrine or paracrine modulator in such 
processes as tumor cell growth, wound repair, neovascularization, and 
inflammation.
    NCI has successfully isolated and cloned the gene that encodes CR-
1, an EGF-related peptide growth factor that does not function through 
the EGF receptor. The NCI has also obtained a rabbit anti-peptide 
polyclonal antibody that can detect the expression of CR-1 in formalin-
fixed, paraffin-embedded human tissue sections. CR-1 has been shown to 
be preferentially and differentially expressed in several different 
human premalignant lesions and cancers. The selected sponsor will 
purify a recombinant CR-1 protein and use this material as an immunogen 
to generate anti-CR-1 monoclonal antibodies for use in the diagnosis 
and prognosis of human cancers.

ADDRESSES: Inquiries and proposals regarding this opportunity should be 
addressed to either Michael Christini or Mark Noel (Tel# 301-496-0477 
Fax# 301-402-2117), Office of Technology Development, National Cancer 
Institute, Bldg. 31, Room 4A49, NIH, 9000 Rockville Pike, Bethesda, MD 
20892.

DATES: Proposals must be received at the above address by 5 P.M. 
September 9, 1994.

SUPPLEMENTARY INFORMATION: The NCI is seeking a pharmaceutical or 
biotechnology company which, after obtaining a license in accordance 
with the requirements of the regulations governing the transfer of 
Government-developed agents (37 CFR part 404), can purify a recombinant 
CR-1 protein for which patents are pending or have been issued and to 
utilize this purified recombinant CR-1 protein as an immunogen to 
generate a panel of mouse monoclonal antibodies. The immunoreactive CR-
1 protein has been detected by immunoperoxidase staining using a rabbit 
anti-peptide polyclonal CR-1 antibody in a majority of human colon 
cancers, breast cancers, gastric cancers and pancreatic cancers. Little 
or no staining was detected in surrounding, noninvolved colon, breast 
or gastric epithelial cells. In addition, a majority of premalignant 
colonic adenomas, breast ductal carcinomas in situ and gastric 
intestinal metaplasia express immunoreactive CR-1.
    A recombinant CR-1 protein has been generated using a yeast 
expression vector in Pichia pastoris and a partially purified protein 
obtained. This protein as well as synthetic, refolded peptides that 
correspond to the EGF-like domain in CR-1 are mitogenic for human 
breast cancer cells yet fail to bind to the EGF receptor or other type 
I receptor tyrosine kinases. Expression of CR-1 antisense mRNA using a 
recombinant, replication defective retroviral expression vector in 
colon cancer cells that expresses CR-1 inhibits the growth of these 
cells in vivo in nude mice. In order to utilize the diagnostic and 
therapeutic potentials of CR-1, it will be necessary to purify a 
significant amount of the recombinant CR-1 protein to more fully define 
its biological properties and to identify the receptor through which it 
functions. In addition, mouse monoclonal antibodies against the 
purified CR-1 recombinant protein will expedite screening studies for 
CR-1 expression in other human premalignant lesions and cancers and 
should exhibit more specificity and sensitivity for the detection of 
CR-1 in tissues by immunocytochemistry (ICC) or in tissue extracts or 
serum samples by ELISA.
    The role of the National Cancer Institute, the Division of Cancer 
Biology, Diagnosis and Centers includes:
    1. NCI will provide expression vectors that encode CR-1 and can be 
used to produce CR-1 in E. coli.
    2. NCI will provide expression vectors that encode CR-1 in yeast 
Pichia pastoris containing several milligrams of recombinant CR-1 
protein.
    3. NCI will provide a rabbit polyclonal anti-CR-1 antibody for 
monitoring CR-1 recovery during the purification from the yeast 
conditioned medium.
    4. NCI will assay the purified recombinant CR-1 protein for 
bioactivity.
    5. NCI will screen anti-CR-1 monoclonal antibodies for reactivity 
by Western blot analysis against native CR-1 protein from CR-1 positive 
human embryonal carcinoma or colon carcinoma cells.
    The role of the successful corporate partner will include:
    1. Obtain background license in appropriate fields of use to the 
relevant Government patent rights.
    2. Purify to homogeneity 30-50 milligrams of CR-1 from Pichia 
pastoris conditioned medium.
    3. Provide the purified recombinant CR-1 protein.
    4. Utilize the purified recombinant CR-1 protein to generate mouse 
anti-CR-1 monoclonal antibodies.
    5. Screen anti-CR-1 monoclonal antibodies for specificity, 
reactivity, and sensitivity towards recombinant CR-1 protein.
    6. Ascertain whether monoclonal anti-CR-1 antibodies can detect 
native CR-1 protein in CR-1 positive human colorectal or embryonal 
carcinoma cells by radioimmunoprecipitation analysis and by ELISA.
    7. Determine whether anti-CR-1 antibodies can be used for ICC on 
formalin-fixed, paraffin embedded tissues known for CR-1 expression.
    8. Provide funds to support a postdoctoral fellow and associated 
expenses.
    Criteria for choosing the collaborating company will include:
    1. Ability to obtain background license to relevant patent rights.
    2. Experience in producing and purifying recombinant proteins, 
particularly growth factors or cytokines.
    3. Experience in generating and screening monoclonal antibodies.
    4. Willingness to cooperate with the NCI in the collection and 
evaluation of data.
    5. Willingness to cost share in laboratory studies.
    6. An agreement to be bound by the DHHS rules involving the use of 
human and animal subjects, and human tissue.
    7. Provisions for equitable distribution of patent rights to any 
inventions. Generally the rights of ownership are retained by the 
organization which is the employer of the free license to the 
Government (when a company employee is the sole inventor) or (2) an 
exclusive or nonexclusive license to the company on terms that are 
appropriate (when the Government employee is the sole inventor).

    Dated: August 8, 1994.
Barbara M. McGarey,
Deputy Director, Office of Technology Transfer.
[FR Doc. 94-19943 Filed 8-15-94; 8:45 am]
BILLING CODE 4140-01-P