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[Federal Register Volume 63, Number 119 (Monday, June 22, 1998)]
[Notices]
[Pages 33937-33939]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-16427]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

Licensing Opportunity and/or Cooperative Research and Development 
Agreement (``CRADA'') Opportunity: Drug and Method To Prevent and Treat 
Graft-Versus-Host Disease and Allograft Rejection

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

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SUMMARY: The NIH is seeking Licensees to further develop, evaluate, and 
commercialize anti-Tac(Fv)-PE38, also known as LMB2. Anti-Tac(Fv)-PE38 
is a recombinant toxin composed of the Fv portion of the anti-Tac 
antibody which binds to the a subunit of the IL2 receptor (also called 
P55, Tac, or CD25) fused to PE38 a mutant form of Pseudomonas Exotoxin 
A. Anti-Tac (Fv)-PE38 is very cytotoxic to normal or malignant cells 
expressing IL2 receptors and is being developed for several proposed 
applications including (1.) the prevention of Graft-versus Host Disease 
(``GVHD'') by purging bone marrow of potentially recipient-reactive 
donor T-cells, (2.) the treatment of Graft-versus Host Disease by i.v. 
administration, and (3.) the treatment or prevention of allograft 
rejection. The goal is to move this methodology into clinical trials. 
The inventions claimed in USPN 4,892,8927, Entitled: ``Recombinant 
Pseudomonas Exotoxins: Construction of an Active Immunotoxin with Low 
Side Effects''; USSN 07/865,722, Entitled: ``Recombinant Antibody-Toxin 
Fusion Protein''; USPN 5,696,237, Entitled: ``Recombinant Antibody-
Toxin Fusion Protein''; and USSN 08/461,825, Entitled: ``Recombinant 
Antibody-Toxin Fusion Protein''; are available for either exclusive or 
nonexclusive licensing for these aforementioned applications (in 
accordance with 35 U.S.C. 207 and 37 CFR Part 404).

DATES: Respondees interested in licensing the invention(s) will be 
required to submit an ``Application for License to Public Health 
Service Inventions'' on or before September 21, 1998 for priority 
consideration.
    Interested CRADA collaborators must submit a confidential proposal 
summary to the NCI on or before September 21, 1998 for consideration. 
Guidelines for preparing full CRADA proposals will be communicated 
shortly thereafter to all respondents with whom initial confidential 
discussions will have established sufficient mutual interest. CRADA 
proposals submitted thereafter may be considered if a suitable CRADA 
Collaborator has not been selected.

ADDRESSES: Questions about licensing opportunities may be addressed to 
J.R. Dixon, Ph.D., Technology Licensing Specialist, Office of 
Technology Transfer, National Institutes of Health, 6011 Executive 
Boulevard, Suite 325, Rockville, Maryland 20852-3804; Telephone: (301) 
496-7056 ext. 206; Facsimile: (301) 402-0220; E-Mail: 
``[email protected]''. Information about Patent Applications and 
pertinent information not yet publicly described

[[Page 33938]]

can be obtained under the terms of a Confidential Disclosure Agreement.
    Depending upon the mutual interests of the Licensee(s) and the NCI, 
a Cooperative Research and Development Agreement (CRADA) to collaborate 
to improve the properties of the Anti-Tac (Fv)-PE38 may also be 
negotiated. Proposals and questions about this CRADA opportunity may be 
addressed to Ms. Karen Maurey, Acting Deputy Director, Technology 
Development & Commercialization Branch, National Cancer Institute, 6120 
Executive Boulevard, Room 450, Rockville, Maryland 20852; Telephone: 
(301) 496-0477; Facsimile: (301) 402-2117. Respondees interested in 
submitting a CRADA. Proposal should be aware that it may be necessary 
to secure a license to the above mentioned patent rights in order to 
commercialize products arising from a CRADA.

SUPPLEMENTARY INFORMATION: Bone marrow transplantation (``BMT'') is an 
useful therapy for the treatment of various malignant and nonmalignant 
genetic and acquired blood disorders which are otherwise incurable. 
However, a significant limitation of using allogeneic BMT is that only 
a minority (less than 30%) of patients have an HLA-identical sibling 
donor. The use of phenotypically matched unrelated donors can only 
partially overcome this problem, mainly because the time needed to 
search for an acceptable donor is often too long for patients with 
advanced disease. Another problem is that ethnic or racial minorities 
are under-represented in the volunteer bone marrow donor registries. As 
a result, the chances of finding an unrelated matched donor for such 
patients is limited.
    Graft-versus-Host disease is one of the most frequent complications 
of allogenic BMT, and is particularly difficult to control in the 
mismatched setting. Not only does severe GVHD impact greatly on the 
quality of life of the transplant recipient, as well as contribute 
significantly to the cost of therapy, but it is the major cause of 
patient mortality either directly or indirectly (e.g. opportunistic 
infections due to long-term immunosuppressive therapy).
    As has been well documented, GVHD is the result of alloreactive T-
cells in the bone marrow graft that are capable of recognizing and 
attacking the tissues of the immunosuppressed recipient. As it also 
known, upon recognition and activation by foreign antigen, T-cells 
express the receptor for interleukine 2 (``LL-2)--which offers a 
possible method for the removal of alloreactive T-cells. If it were 
possible to eliminate the presence of contaminating recipient-
alloreactive T-cells in the bone marrow graft, thus preventing or 
reducing the severity of GVHD, allogeneic transplantation might find 
greater applications and use in the treatment of a variety of other 
diseases (e.g., autoimmune diseases such as rheumatoid arthritis, 
etc.). In cases where haploidentical related donors may be readily 
available to serve as a donor, specific T-cell depletion would permit 
the haploidentical donor's immunity to be transferred with the graft 
while preventing severe GVHD, thus improving the overall patient 
outcome
    While GVHD can be prevented by extensive non-selective T-cell 
depletion of the bone marrow graft, this procedure increases the risk 
of infection and graft rejections. In HLA genotypically identical 
sibling transplant, GVHD can be controlled somewhat through the use of 
immunosuppressive therapy (e.g., Cyclosporin, Methotrexate, etc.). 
However, such therapeutic modalities are much less effective in the 
mismatched setting and are associated with susceptibility to bacteria 
and viral infections, development of new malignancies, and end organ 
failure.
    NIH/NCI scientists at the National Cancer Institute have developed 
and evaluated in animal models, a recombinant immunotoxin (e.g., Anti-
Tac (Fv)/PE38) which kills activated T-cells at very low immunotoxin 
concentrations. The subject Immunotoxin is a single chain protein 
composed of the Fv portion of an antibody fused to the amino terminus 
of the PE. The toxin has three domains: IA is responsible for cell 
binding, II is required for translocation and has the proteolytic 
processing site, and III has the ADP-ribosylating activity. After call 
internalization, a truncated form of PE, generated by proteolytic 
cleavage translocates to the cytosol where ADP-ribosylation of 
elongation factor 2 terminates protein synthesis causing cell death.
    NIH/NCI scientists have shown that Anti-Tac(Fv)-PE38 may prevent 
and reduce the severity of GVHD by specific elimination or reduction of 
recipient-alloreactive donor T-cells without adversely affecting other 
T-cell population or compromising stem cell engraftment and recipient 
hematopoietic rescue and survival. These experiments have demonstrated 
that it is possible to inexpensively and selectively eliminate or 
reduce the numbers of alloreactive T-cells present in a bone marrow 
graft resulting in prevention of or a reduction in the severity of GVHD 
after bone marrow transplantation procedures, but does not compromise 
stem cell engraftment and recipient hematopoietic rescue and survival. 
The methodology is simple and does not involve significant lengths of 
time or specialized equipment. Thus it should be possible to transition 
these findings to the clinical situation without significant problems. 
If clinical results approximate the observed animal finding it might 
then be possible to utilize BMT in many other disease conditions.
    In addition NIH/NCI scientists have shown in a Phase I Trial that 
Anti-Tac(Fv)-PE38 can be safely administered intravenously to patients 
with cancer; good blood levels of the immunotoxin are also achieved. 
Thus Anti-Tac(Fv)-PE38 may also be used to treat patients with GVHD or 
the treat patients undergoing allograft rejection.
    A Cooperative Research and Development Agreement or CRADA means the 
anticipated joint agreement to be entered into by NCI pursuant to the 
Federal Technology Transfer Act of 1986 and Executive Order 12591 of 
April 10, 1987 as amended by the National Technology Transfer 
Advancement Act of 1995 to collaborate to improve the properties of 
Anti-Tac(Fv)-PE38. The expected duration of the CRADA would be from one 
(1) to five (5) years.
    The role of the NCI in the CRADA may include, but not be limited 
to:
    1. Providing intellectual, scientific, and technical expertise and 
experience to the research project.
    2. Providing the Collaborator with samples of the subject compounds 
to create, optimize, test and develop targeted drugs for clinical 
studies.
    3. Planning research studies and interpreting research results.
    4. Carrying out research to improve the properties of Anti-Tac(Fv)-
PE38 which include, but are not restricted to, increased production 
yield, decreased side effects, increased cyotoxic activity and better 
tissue penetration.
    5. 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. Planning research studies and interpreting research results.
    3. Providing samples of the subject compounds to create, optimize, 
test and develop targeted drugs for clinical studies.
    4. Providing technical and/or financial support to facilitate 
scientific goals and for further design of

[[Page 33939]]

applications of the technology outlined in the agreement.
    5. Providing immunotoxin for laboratory and animal studies.
    6. 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 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 ongoing research 
and development.
    2. The demonstration of adequate resources to perform the research 
and development 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 and development of this technology, as outlined in the 
CRADA Collaborator's proposal.
    4. The demonstration of expertise in the commercial development and 
production of products related to this area of technology.
    5. The level of financial support the CRADA Collaborator will 
provide for CRADA-related Government activities.
    6. The demonstration of expertise pertinent to the development of 
models to evaluate and improve the efficacy of immunotoxin in the 
prevention or treatment of graft-versus-host disease and/or allograft 
rejection.
    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 distribution of patent rights to CRADA inventions. 
Generally, the right 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 for an 
option to elect an exclusive or nonexclusive license to the CRADA 
Collaborator when the Government employee is the sole inventor.

    Dated: June 11, 1998.
Kathleeen Sybert,
Acting Director, Technology Development and Commercialization Branch, 
National Cancer Institute, National Institutes of Health.

    Dated: April 30, 1998.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 98-16427 Filed 6-19-98; 8:45 am]
BILLING CODE 4140-01-M
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