Federal Register announcement, spring 1996

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

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

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 pm
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
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 clincally. 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 pancarcinoma 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 111In and developed OncoScint 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 125I-labeled murine
CC49 with an intraoperative hand held probe as a method of
radioimmunoguided surgery.


 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

 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.

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
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 cell 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
3) Collaborate on data analysis in support of clinical trials.

Proposals submitted for consideration should fully address each
of the following qualifications:
1) Experience in the GMP production, purification, quality
control or 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.
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
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.

Source: 60 FR 20276
(Published in Federal Register 4/25/95)