[Federal Register Volume 69, Number 173 (Wednesday, September 8, 2004)]
[Notices]
[Pages 54293-54295]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-20291]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


National Cancer Institute: Cooperative Research and Development 
Agreement (``CRADA'') Opportunity and Licensing Opportunity: Scientific 
and Commercial Drug Development To Exploit Antiangiogenic Activity 
Targeting Adrenomedullin Gene Products

AGENCY: National Institutes of Health, Public Health Service, DHHS.

ACTION: Notice.

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SUMMARY: The National Cancer Institute (NCI) is currently seeking 
Cooperative Research and Development Agreement (CRADA) collaborator(s) 
to work with investigators in the Center for Cancer Research (CCR) to 
explore, for drug development and clinical testing, novel 
antiangiogenic agents that target adrenomedullin gene products. 
Research and development may include development of blocking reagents 
(humanized antibodies, peptide antagonists, small molecules), 
formulation for systemic and topical application, preclinical animal 
studies, and clinical trials. Licensing is available for background 
inventions related to this technology.

DATES: Parties interested in a CRADA collaboration should notify the 
Technology Transfer Branch of the NCI in writing of their interest no 
later than October 25, 2004. The written notice should briefly address 
the selection criteria listed below under Supplementary Information.

[[Page 54294]]

    Licensing inquiries/applications are accepted by the NIH Office of 
Technology Transfer at any time.

ADDRESSES: For information on the CRADA Opportunity, please contact: 
Julianne Chappell, J.D., Technology Transfer Specialist, Technology 
Transfer Branch, National Cancer Institute, NIH, 6120 Executive 
Boulevard, Suite 450, Rockville, MD 20852; Phone: (301) 496-0477; Fax: 
(301) 402-2117; e-mail: [email protected].
    For information on the Licensing Opportunity, please contact: 
Pradeep Ghosh, J.D., Ph.D., M.B.A., Technology Licensing Specialist, 
Office of Technology Transfer, National Institutes of Health, 6011 
Executive Blvd., Suite 325, Rockville, MD 20852; Phone: (301) 435-5282; 
Fax: (301) 402-0220; e-mail: [email protected]. Information about 
patent application(s) and pertinent information not yet publicly 
described can be obtained under the terms of a Confidential Disclosure 
Agreement. Respondees interested in licensing the technology will be 
required to submit an Application for License to Public Health Service 
Inventions.

SUPPLEMENTARY INFORMATION:
    Scientific Background: Tumor growth requires a series of 
extracellular signaling molecules that induce cell proliferation and 
production of new blood vessels (angiogenesis) and reduce apoptosis 
(programmed cell death) of the tumor cells. Agents that block 
angiogenesis or tumor cell proliferation have been successfully used in 
the clinic to reduce tumor burden.
    The regulatory peptide adrenomedullin (AM) is a multifunctional 
molecule that has been recently characterized by researchers at the 
CCR, through use of ex vivo and in vivo animal models, as a 
proangiogenic factor. In addition to inducing angiogenesis, AM 
functions in cancer cells as an autocrine growth factor, enhances 
thymidine incorporation, reduces apoptosis, and is induced by hypoxia, 
thus identifying this peptide as an important tumor cell survival 
factor and a potential target for antitumor therapy.
    AM is synthesized as a prohormone that contains another 
biologically active peptide, proAM N-terminal 20 peptide. CCR has 
determined that PAMP is approximately one million times more potent 
than well-known angiogenic factors such as vascular endothelial growth 
factor (VEGF) and basic fibroblast growth factor (bFGF). CCR scientists 
have characterized PAMP's angiogenic activity in both in vitro and in 
vivo assays, including a chick aortic ring angiogenesis assay and a 
nude mouse angiogenesis assay. Inhibitors of PAMP have been shown to 
inhibit angiogenesis in vivo.
    Current Status of the Technology: There is a continuing market need 
for new therapeutic interventions to inhibit angiogenesis in diseases 
dependent on the development of new vasculature, or to promote 
angiogenesis in conditions ameliorated by such development. In addition 
to the discoveries described above, CCR scientists have developed a 
method of screening small molecule libraries for AM agonists and 
antagonists and have identified a number of potential small molecule 
candidates for drug development; CCR has also identified antagonistic 
peptide fragments and monoclonal antibodies against AM and PAMP that 
may warrant development. These discoveries form the basis of the 
background intellectual property, identified below in the Patent Status 
and Pertinent References section. AM gene products and their agonists 
or antagonists may prove effective in areas such as cancer treatment, 
wound healing, diabetic retinopathy, endometriosis, psoriasis, 
arthritis, coronary artery disease, peripheral vascular disease, and 
cerebral ischemia.
    CRADA Proposal: CRADA collaborative efforts will explore the 
specific and highly active pathway discussed above. Inhibition of 
either AM or PAMP in vivo with a variety of agents (monoclonal 
antibodies, peptide analogs, small molecule antagonists) results in 
significant reduction of tumor growth. Therefore, CRADA studies may 
focus on the utilization of that technology in tumor management, and 
the NCI proposal delineated below reflects that approach. The 
Institute, however, is open to proposals directed at other diseases and 
conditions in which angiogenesis may play a major role (arthritis, 
impaired wound healing, ischemia, retinal degeneration, coronary artery 
disease, etc).
    Proposed NCI Contribution: The role of the NCI will include, but 
not be limited to, the following:
    1. Conduct in vitro and in vivo analysis of the antitumor 
capabilities of the generated blocking reagents.
    2. Test biological specimens from the animal and clinical phases to 
evaluate whether the intermediate endpoints (diminution of peptide 
contents) are reached.
    Proposed CRADA Collaborator Contribution: The role of the CRADA 
collaborator(s) will include, but not be limited to, the following:
    1. Manufacture enough of the blocking reagents (humanized 
monoclonal antibodies, peptide antagonists, small molecules) under FDA 
approved standards.
    2. Formulate the initial lot of agent for topical and systemic 
administration.
    3. Perform pharmacokinetic and pharmacodynamic evaluation in animal 
models.
    4. Collaborate in the planning and support clinical development 
leading to FDA approval and marketing.
    5. Conduct clinical trials.
    Proposed Joint Contribution: NCI and CRADA collaborator(s) will:
    1. Design a CRADA research plan and interpret the data generated 
under the research plan.
    2. Publish the results and share all data as soon as they become 
available.
    Selection Criteria for Choosing the CRADA Collaborator May Include:
    1. A demonstrated background and expertise in conducting clinical 
trials, and in the generation of the blocking reagents.
    2. The demonstration of adequate resources to perform the research 
and development necessary for commercialization of the technology and 
any inventions.
    3. A demonstrated record of success in the commercial development 
and production of products related to this area of technology.
    4. The level of financial and staffing support the CRADA 
collaborator will provide for CRADA-related activities.
    5. The willingness to cooperate with the NCI in the collection, 
evaluation, and maintenance of data from preclinical and clinical 
trials of investigational agents; and in the timely publication of 
research results.
    6. The agreement to be bound by the Department of Health and Human 
Services (DHHS) regulations involving the use of human and animal 
subjects, and human tissue.
    7. The willingness to accept the legal provisions and language of 
the CRADA. These provisions govern the distribution of future patent 
rights to CRADA inventions. Generally, the rights of ownership are 
retained by the organization which is the employer of the inventor, 
with (a) 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 (b) 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.
    8. The willingness to obtain any necessary background licenses to 
NIH technology.
    Terms/Licensing Potential/Patent Status:

[[Page 54295]]

    1. No funding from the Government is available to collaborator 
under a CRADA.
    2. Non-exclusive license option available for background rights. 
Exclusive license rights may be available in a specified field of use.
    3. One patent has been issued related to Adrenomedullin and PAMP 
and other related patent applications are pending.
    4. In case, as a result of the CRADA work, a joint intellectual 
property is developed, the CRADA partner may have a right to file a 
joint patent application.
    Patent Status and Pertinent References:
    U.S. Provisional Patent Application Number 60/425,018, filed 
November 7, 2002, ``A New Target for Angiogenesis and Anti-angiogenesis 
Therapy.''
    Patent Application Number PCT/US2003/035633, filed November 7, 
2003, ``A New Target for Angiogenesis and Anti-angiogenesis Therapy.''
    U.S. Provisional Application Serial No. 60/500,650 filed on 09/08/
2003; ``A new method to screen small molecule libraries and 
biologically active compounds that modulate adrenomedullin and gastrin 
releasing peptides.'' International Publication Number WO 2004/043383 
A2, published May 27, 2004, ``A New Target for Angiogenesis and Anti-
angiogenesis Therapy.''
    L[oacute]pez J, Mart[iacute]nez A. Cell and molecular biology of 
the multifunctional peptide, adrenomedullin. International Review of 
Cytology 221:1-92 (2002).
    Mart[iacute]nez A, Vos M, Gu[eacute]dez L, Kaur G, Chen Z, Garayoa 
M, P[iacute]o R, Moody T, Stetler-Stevenson WG, Kleinman HK, Cuttitta 
F. The effects of adrenomedullin overexpression in breast tumor cells. 
Journal of the National Cancer Institute 94: 1226-1237 (2002).
    Cuttitta F, P[iacute]o R, Garayoa M, Zudaire E, Juli[aacute]n M, 
Elsasser TH, Montuenga LM, Mart[iacute]nez A. Adrenomedullin functions 
as an important tumor survival factor in human carcinogenesis. 
Microscopy Research and Technique 57:110-119 (2002).
    P[iacute]o R, Mart[iacute]nez A, Cuttitta F. Cancer and diabetes: 
two pathological conditions in which adrenomedullin may be involved. 
Peptides 22:1719-1729 (2001).
    P[iacute]o R, Mart[iacute]nez A, Unsworth EJ, Kowalak JA, 
Bengoechea JA, Zipfel PF, Elsasser TH, Cuttitta F. Complement factor H 
is a serum binding protein for adrenomedullin. The resulting complex 
modulates the bioactivities of both partners. Journal of Biological 
Chemistry 276:12292-12300 (2001).
    Mart[iacute]nez A, Juli[aacute]n M, Bregonzio C, Notari L, Moody 
TW, Cuttitta F. Identification of vasoactive non-peptidic positive and 
negative modulators of adrenomedullin using a neutralizing monoclonal 
antibody-based screening strategy. Endocrinology 145:3858-3865 (2004).
    Mart[iacute]nez A, Zudaire E, Portal-N[uacute]nez S, Gu[eacute]dez 
L, Libutti SK, Stetler-Stevenson WG, Cuttitta F. Proadrenomedullin--
terminal 20 peptide is a potent angiogenic factor and its inhibition 
results in reduction of tumor growth. Cancer Research in press (2004).

    Dated: August 25, 2004.
Karen Maurey,
Acting Chief, Technology Transfer Branch, National Cancer Institute, 
National Institutes of Health.
    Dated: August 30, 2004.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 04-20291 Filed 9-7-04; 8:45 am]
BILLING CODE 4140-01-P