[Federal Register Volume 60, Number 79 (Tuesday, April 25, 1995)]
[Notices]
[Pages 20276-20278]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-10110]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health


National Cancer Institute: Opportunity for a Cooperative Research 
and Development Agreement (CRADA) for the Scientific and Commercial 
Development of Monoclonal Antibodies for the Therapy and/or Diagnosis 
of Cancer

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Advertisement.

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SUMMARY: The Laboratory of Tumor Immunology and Biology (LTIB), 
National Cancer Institute is seeking pharmaceutical or biotechnology 
collaborator(s) which can effectively pursue the scientific and 
commercial development of a panel of monoclonal antibodies generated 
against tumor associated antigens for use in the therapy and/or 
diagnosis of a range of human cancers. The primary focus of these 
collaborations will be the development and commercialization of a panel 
of monoclonal antibodies consisting of two major groups: (A) Monoclonal 
antibodies directed against the pancarcinoma antigen, TAG-72. TAG-72 is 
expressed on a range of human carcinomas including colorectal, gastric, 
pancreatic, ovarian, endometrial, breast, non-small cell lung, and 
prostate. Monoclonal antibody CC49 is the prototype monoclonal antibody 
of this group. Humanized and other genetically engineered variants of 
monoclonal antibody CC49 have already been developed. (B) Monoclonal 
antibodies directed against human carcinoembryonic antigen, which is 
expressed on the following carcinomas: colorectal, pancreatic, gastric, 
non-small cell lung, and breast carcinoma. The prototype for this group 
of monoclonal antibodies is COL-1. (C) Additionally, it may likely be a 
further goal of these collaborations to develop novel recombinant forms 
of these monoclonal antibodies.
    It is anticipated that because of the magnitude, diversity, and 
expense of these proposed research projects the collaboration(s) may 
take the form of multiple CRADAs. The collaboration(s) will involve all 
aspects of diagnostic and/or therapeutic development from basic 
scientific inquiry to late stage clinical trials which selected 
sponsor(s) will be required to partially support. The selected 
sponsor(s) will collaborate in the development of one or more of the 
following diagnostic or therapeutic forms of these monoclonal 
antibodies: (1) Radiolabeled monoclonal antibodies (diagnostic 
(oncologic imaging) and/or therapeutics); (2) Drug and/or toxin 
conjugated monoclonal antibodies; (3) Pro-drug conjugated monoclonal 
antibodies; (4) Unconjugated monoclonal antibodies (including 
bifunctional forms).
    Sponsors will be selected based upon their ability to collaborate 
with NCI for the development of any of these therapeutic or diagnostic 
forms in accordance with the corporate role and selection criteria 
outlined below. It is emphasized that selection of a collaborator will 
not be dependent upon an entity's ability to perform the largest 
portion of the research project. Rather, a collaborator will be 
selected based upon the scientific merit and intellectual contributions 
brought to each individual project(s). Potential collaborators are, 
therefore, urged to submit proposals which focus on particular area(s) 
of expertise in a well-organized and precise manner which clearly 
outlines a development and commercialization plan. Finally, it is also 
possible that logical extensions of these research protocols may be 
considered as potential collaborative projects. Accordingly, proposals 
must address the requested criteria and protocols, but in addition, may 
include any additional unique development projects relating to the core 
technology.
    The term of the CRADA(s) is anticipated to be three (3) to five (5) 
years.

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, Building 31, Room 4A49, NIH, 9000 Rockville Pike, Bethesda, 
MD 20892.

DATES: Proposals must be received at the above address by 5 p.m. June 
26, 1995.

SUPPLEMENTARY INFORMATION: 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 October 10, 1987 to collaborate on 
the specific research project described below. Under the present 
proposal, the Government is seeking collaborator(s), which in 
accordance with the requirements of the regulations governing the 
transfer of technology in which the Government has taken an active role 
in developing (37 CFR 404.8), can further develop this technology to a 
commercially available status to best meet the needs of the public.
    This technology has been the focal point of much research and 
[[Page 20277]] development within the LTIB for many years. During that 
time, there has been continual advances in the field of antibody 
development within LTIB via extensive intramural research, corporate 
sponsored CRADA projects, and independent corporate development under 
licensing arrangements.
    When the excellent tumor targeting characteristics of anti-TAG-72 
monoclonal antibody B72.3 in the clinic were observed, the LTIB 
developed a series of second generation, higher affinity monoclonal 
antibodies for TAG-72. This ``CC'' series, of which monoclonal antibody 
CC49 is the prototype, has been extensively characterized both 
preclinically and clinically. Radiolabeled CC49 shows much better tumor 
targeting in the clinic than B72.3. CC49 reacts with the majority of 
the following carcinomas: Colorectal, gastric, pancreatic, non-small 
cell lung, ovarian, endometrial, breast and prostate.
    The LTIB has also developed a series of anti-carcinoembryonic 
antigen monoclonal antibodies (COL series). The prototype (COL-1) 
reacts to the vast majority of gastrointestinal and pancreatic cancers, 
and also to 50% of breast cancers and 70% of non-small cell lung 
cancers. A Phase 1 trial has just been completed with radiolabeled COL-
1.
    The LTIB has shown successful tumor targeting in cancer patients 
with radiolabeled forms of both monoclonal antibodies which are the 
primary focus of these collaborations: CC49 and COL-1. Phase I therapy 
trials for both monoclonal antibodies have been completed. 
Additionally, radiolabeled forms of CC49 are currently in Phase II 
clinical trials for colorectal, breast, ovarian, and prostatic cancer 
as a murine monoclonal antibody.
    As a corollary, the progression of the technology can be 
illustrated in two specific examples of ongoing research collaborations 
which will not be a part of the present CRADA:
    (A) The LTIB, NCI initially developed a monoclonal antibody 
designated B72.3, which reacts to the pancacinoma antigen termed TAG-
72. This breakthrough technology provided the basis for the first and 
still only monoclonal antibody approved by the FDA for any in vivo use 
in cancer. Under a separate licensing agreement, Cytogen Corporation 
conjugated B72.3 with\111\ In and developed Onco Scint CR/OV 
for oncologic imaging to be used in conjunction with CT scan. OncoScint 
CR/OV has been approved for use in both colorectal cancer and 
ovarian cancer.
    (B) Under a separate CRADA agreement, a Phase III multicenter trial 
is also in progress employing\125\ I-labeled murine CC49 with an 
intraoperative hand held probe as a method of radioimmunoguided 
surgery.

Additional Background Information

     The LTIB has shown via immunohistochemistry that anti-TAG-
72 and anti-carcinoembryonic antigen monoclonal antibodies complement 
each other extremely well in overcoming antigen heterogeneity. Serum 
assays for carcinoembryonic antigen and TAG-72 (CA72-4) are also 
complementary in that non-coordinate expression is observed.
     Previous collaborative studies on the use of the CC49 and 
COL-1 monoclonal antibodies as drug conjugates demonstrated anti-tumor 
effects in animal models.
     The LTIB has recently developed CDR grafted (humanized) 
forms of monoclonal antibody CC49, and other novel genetically 
engineered immunoglobulin forms for CC49 could be the subject of any 
CRADA. Similar constructs of anti-carcinoembryonic antigen monoclonal 
antibodies could also be the subject of any CRADA.
     Recent clinical trials have supported the preclinical 
observations that recombinant interferon will selectively upregulate 
both TAG-72 and carcinoembryonic antigen expression on the surface of 
tumor cells. This finding should enhance both diagnostic and 
therapeutic uses of these classes of monoclonal antibodies, and these 
studies could be included as CRADA activities.
     The NIH has exclusively licensed the rights for monoclonal 
antibody CC49 for use with the radioimmunoguided surgery intraoperative 
probe as part of a separate collaboration.
     A comprehensive list of publications relating to this 
technology, intellectual property and background licensing information, 
and general CRADA information will be provided upon initial contact 
with NCI.

Party Contributions

    The role of the National Cancer Institute includes the following:
    (1) Develop novel recombinant forms of monoclonal antibodies.
    (2) Initial characterization of hybridoma cell lines producing 
monoclonal antibodies.
    (3) Conduct preclinical testing (tumor targeting and therapy) of 
these monoclonal antibodies both in vivo and in vitro as unlabeled 
immunoglobulin forms and/or as antibody conjugates.
    (4) Conduct preclinical studies on the use of biologic response 
modifiers to upregulate tumor targeting and therapy.
    (5) Analyze pharmacokinetics and anti-immunoglobulin responses in 
some clinical trials.
    The role of the successful corporate sponsor(s) will include:
    (1) Develop high producer clones of the monoclonal antibodies and 
recombinant immunoglobulin producing cells lines and cultures supplied 
by the NCI and optimize production and purification procedures for 
experimental tumor targeting and therapy studies.
    (2) Produce and purify clinical grade (GMP) monoclonal antibodies 
for clinical trials and submit Drug Master Files in support of the 
monoclonal antibody production.
    (3) Conduct toxicity studies as required by the FDA.
    (4) Develop methodologies for the conjugation of monoclonal 
antibodies with (A) Radionuclides, (B) Drugs and/or toxins, (C) Pro-
drugs, (D) Bifunctional antibodies.
    (5) Submit IND application in support of clinical trials.
    (6) Conduct clinical trials using monoclonal antibody and 
immunoglobulin forms.
    The role of both the National Cancer Institute and the successful 
corporate sponsor(s) will include:
    (1) Optimize purification schemes for immunoglobulin forms, prior 
to and post conjugation.
    (2) Collaborate on clinical trial design including protocols using 
biologic response modifiers (e.g., recombinant interferon).
    (3) Collaborate on data analysis in support of clinical trials.

Selection Criteria

    Proposals submitted for consideration should fully address each of 
the following qualifications:
    (1) Experience in the GMP production, purification, quality control 
of monoclonal antibodies and regulatory requirements of monoclonal 
antibody clinical trials.
    (2) Experience in the conjugation of monoclonal antibodies with one 
or more of the following: (A) Radionuclides, (B) Drugs and/or toxins, 
(C) Pro-drugs, (D) Bifunctional Antibodies and the analyses of these 
reagents.
    (3) Ability to provide necessary reagents on a timely basis.
    (4) Experience in conducting clinical trials.
    (5) Willingness to cooperate with the National Cancer Institute in 
the collection and evaluation of data. [[Page 20278]] 
    (6) Agreement to be bound by the DHHS rules involving the use of 
human and animal subject, and human tissue.
    (7) Ability to obtain background license to relevant patent rights.
    (8) Willingness to agree to Federal Statutory provisions for the 
equitable distribution of patent rights to any CRADA subject-matter 
inventions. Generally, the rights of ownership are retained by the 
organization which is the employer of the inventor, with (A) an 
irrevocable, non-exclusive, royalty-free research license to the 
Government (when a company employee is the sole inventor) or (B) an 
option for an exclusive or non-exclusive license to the company on 
terms that are appropriate (when the Government employee is the sole or 
joint inventor).
    (9) Willingness to cost share in laboratory studies including the 
funding of personnel dedicated to completion of the CRADA research 
project.
    (10) Submission of an initial response to the NIH Model CRADA 
boilerplate provisions.

    Dated: April 13, 1995.
Dr. Thomas Mays,
Director, Office of Technology Development, National Cancer Institute, 
National Institutes of Health.
[FR Doc. 95-10110 Filed 4-24-95; 8:45 am]
BILLING CODE 4140-010-P