[Federal Register Volume 63, Number 229 (Monday, November 30, 1998)]
[Notices]
[Pages 65796-65798]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-31733]


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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 For The Therapeutic 
Treatment of Lymphomas And Leukemias

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

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SUMMARY: The NIH is seeking Licensee(s) and/or a Cooperative Research 
and Development Agreement (``CRADA'') to further develop, evaluate, and 
commercialize a recombinant immunotoxin, termed RFB4(dsFv)-PE38

[[Page 65797]]

or BL22, for use in the therapeutic treatment of lymphomas and 
leukemias. RFB4(dsFv)-PE38 (BL22) is a disulfide-linked recombinant 
immunotoxin fused to PE38, a mutant form of Pseudomonas Exotoxin (PE), 
that binds to CD22--a 135kDa phosphoglycoprotein adhesion molecule 
present on the surface of B-cells. RFB4 is a mouse monoclonal antibody 
that recognizes an external epitope on the CD22 cell surface antigen 
and has no detectable cross-reactivity with any other normal cell 
types. CD22 is a lineage-restricted B-Cell antigen that belongs to the 
Ig superfamily and is displayed on chronic B-Lymphocytic Leukemia cells 
and B-cell Non-Hodgkins Lymphoma cells. To kill CD22-positive cells, 
the RFB4 antibody was used to make a recombinant immunotoxin. To 
construct the recombinant PE immunotoxin, the variable portions of the 
heavy and light chains of RFB4 were cloned and the Fv fragments linked 
together by a disulfide bond to form a disulfide stabilized (ds) 
construct. The construct was combined by gene fusion with PE38, a 
truncated version of PE, to form RFB4(dsFv)-PE38, or BL22.
    The inventions are claimed in USPN 4,892,827, 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''; and 
are available for either exclusive or non-exclusive licensing for these 
aforementioned applications only (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 March 1, 1999.
    Interested CRADA collaborators must submit a confidential proposal 
summary to the National Cancer Institute (``NCI'') on or before March 
1, 1999, 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)-402-0200; E-Mail 
``[email protected]''. Information about Patent Applications and 
pertinent information not yet publicly described can be obtained under 
the terms of a Confidential Disclosure Agreement. Respondees interested 
in licensing the invention(s) will be required to submit an 
``Application for License to Public Health Service Inventions''.
    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 RFB4(dsFv)-PE38 immunotoxin may also 
be negotiated. Proposals and questions about this CRADA opportunity may 
be addressed to Dr. Patrick Twomey, Technology Development Specialist, 
Technology Development & Commercialization Branch, National Cancer 
Institute, 6120 Executive Plaza South-Room 450, Rockville, Maryland 
20852; Telephone: (301)-496-0577; Facsimile: (301)-402-2117; email: 
[email protected]. 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: NIH/NCI scientists have done toxicity 
studies with the RFB4(dsFv)-PE38 immunotoxin in mice and cynomolgus 
monkeys. The immunotoxin is toxic for CD22 positive cells and exhibits 
antitumor activity in nude mice bearing human B-cell lymphomas. The 
IC50 of BL22 against four Burkitt's lymphoma cell lines 
range from 0.25-1.5 ng/ml. The dose in mice producing complete 
regression of subcutaneous CA46 lymphomas was 275 g/kg on an 
alternate daily X 3 schedule (WODX3). The LD50 in tumors was 
approximately 1,303 g/kg and the maximum tolerated dose was 
400 g/kg/dose. Pilot studies in cynomolgus monkeys showed no 
dose limiting toxicity at doses up to 2,000 g/kg QODX3 by i.v. 
bolus. Peak plasma levels were 2.5, 10, and 55 g/mL in monkeys 
treated with 100 g/kg, 500 g/kg and 2,000 g/
kg BL22, respectively. BL22 was eliminated nonexponentially from plasma 
with a half-life of approximately 44 to 66 minutes.
    In the United States, Non-Hodgkin's lymphomas have a 1998 expected 
incidence of 55,400 including 24,900 expected deaths. The incidence of 
Non-Hodgkin's lymphomas has risen 50% during the last 15 years, 
including 3-4%/year recently, making it one of the most rapidly 
increasing malignancies in terms of incidence. Chronic lymphocytic 
leukemias have a 1998 incidence of 7,300 cases with 4,800 deaths. Thus 
approximately 50,000 patients per year in the U.S. are diagnosed with 
CD22+ malignant disease, half of which cannot be effectively treated 
with known modalities. This makes CD22+ malignancies a major public 
health problem in the U.S. and an appropriate target for newer targeted 
approaches. Hence, the development of new therapeutic modalities, such 
as RFB4(dsFv)-PE38, to treat these malignancies is needed.
    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 the 
RFB4(dsFv)-PE38 immunotoxin. 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 the 
RFB4(dsFv)-PE38 which include, but are not restricted to, increased 
production yield, decreased side effects, increased cytotoxic activity 
and better tissue penetration.
    5. Publishing research results.
    The role of the CRADA Collaborator may include, but not be limited 
to:
    1. Providing sufficient amounts of BL22 for clinical trials.
    2. Conducting Phase 2 and Phase 3 clinical trials.
    3. Providing significant intellectual, scientific, and technical 
expertise or experience to the research project.
    4. Planning research studies and interpreting research results.
    5. Providing samples of the subject compounds to create, optimize, 
test and develop targeted drugs for clinical studies.
    6. Providing technical and/or financial support to facilitate 
scientific goals and for further design of

[[Page 65798]]

applications of the technology outlined in the agreement.
    7. Incorporating the immunotoxin into formulations in order to 
increase the therapeutic efficacy and decrease immunogenicity.
    8. Providing immunotoxin for laboratory and animal studies.
    9. 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 the RFB4 (dsFv)-PE38 
immunotoxin for the treatment of lymphomas and leukemias.
    7. The demonstration of expertise in the formulation of drugs.
    8. The willingness to cooperate with the NCI in the timely 
publication of research results.
    9. 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.
    10. 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 rights 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 of 
an option to elect an exclusive or nonexclusive license to the CRADA 
Collaborator when the Government employee is the sole inventor.

    Dated: November 5, 1998.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
    Dated: November 16, 1998.
Kathleen Sybert,
Acting Director, Technology Development and Commercialization Branch, 
National Cancer Institute, National Institutes of Health.
[FR Doc. 98-31733 Filed 11-27-98; 8:45 am]
BILLING CODE 4140-01-M