[Federal Register Volume 72, Number 184 (Monday, September 24, 2007)]
[Notices]
[Pages 54274-54275]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-18771]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Public Teleconference Regarding Licensing and Collaborative 
Research Opportunities for: Novel Ligands for Diagnostic Imaging and 
Radioimmunotherapy; Dr. Martin Brechbiel et al. (NCI)

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

ACTION: Notice

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Technology Summary

    The technology describes the composition of several 1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 
diethylenetriaminepentaacetic acid (DTPA) compounds, their synthesis, 
metal complexes, conjugates, and their application in diagnostic 
imaging and radioimmunotherapy.

Technology Description

    Monoclonal antibodies (mAbs) have been employed as targeting 
biomolecules for the delivery of radionuclides into tumor cells in 
radioimmunotherapy (RIT). Numerous clinical trials have been performed 
to validate this modality of cancer therapy.
    While one critical variable that influences the effectiveness of 
RIT is the choice of the radionuclide and its

[[Page 54275]]

associated emission characteristics, an equally important aspect is the 
choice of the chemical means by which the radionuclide is bound to the 
protein. For RIT applications, radioisotopes such as \90\Y (Yttium-90) 
or \177\Lu (Lutetium-177) must be linked as a metal complex to a 
monoclonal antibody (mAb) or immunoprotein via a suitable bifunctional 
chelating agent, wherein that complex must be thermodynamically and 
kinetically stable to minimize release of the isotope in order to 
minimize toxicity in vivo. Compounds that can easily conjugate as metal 
complexes, and are stable to an extent in vivo are needed for new 
imaging diagnostics and radiotherapy technologies.
    In general, DOTA conjugated to mAbs display relatively slow and 
inefficient radiolabeling with Y(III) isotopes under mild conditions. 
This is contrary to the rapid and high-yield radiolabeling (>90%) of 
mAbs conjugated with bifunctional derivatives of the acyclic chelating 
agent DTPA.
    Since the release of the radiometal from the chelate is a potential 
source of radiotoxic effects to non-tumor cells and normal tissue, a 
chelate that forms a kinetically inert complex with the radiometal is 
critical for successful targeted radiotherapy. Additionally, compounds 
having complex stability comparable to that of DOTA and complexation 
kinetics characteristics of DTPA are desirable for effective 
conjugation and in vivo efficacy.
    This technology family describes the synthesis of several DOTA and 
DTPA based compounds. The technology family consists of three different 
types of compounds: (1) Backbone-substituted DOTA compounds, metal 
complexes, and conjugates (2) two protected variants of the 2-(4-
isothiocyanatobenzyl)-6-methyldiethylenetriamine pentaacetic acid 
(1B4M-DTPA), (3) a protected active ester variant of the CHX-A'' DTPA 
and (4) Substituted 1,4,7-triazacyclononane-N,N',N''-triacetic acid 
(NOTA) compounds with a pendant donor amino group, metal complexes, 
having the properties of both DOTA and DTPA.
    More specifically, the NOTA compounds are substituted 1,4,7-
triazacyclononane-N,N',N''-triacetic acid compounds with a pendant 
donor amino group. These compounds possess the same octadentate 
coordinating groups as DOTA and DTPA; however, these compounds have a 
combined macrocyclic and acyclic character. The macrocyclic component 
chosen is based upon 1,4,7-triazacyclononane-N,N',N''-triacetic acid 
(``NOTA''), while the acyclic component is a pendant 
bis(carboxymethyl)amino donor group that is connected by an alkylene 
bridge that is optionally substituted with an aralkyl group. The 
cooperative binding of the pendant donor groups coupled with the pre-
organization and macrocyclic effect of the NOTA sub-structure 
accelerates complexation with metal ions and isotopes (e.g., Y(III), Gd 
(III)) while maintaining a high level of stability of the complexes.
    The 1B4M-DTPA and the CHX-A'' molecules were synthesized for the 
following uses: (1) Use in the introduction of the chelator to the N-
terminus of peptides, aptamers, PNA, wherein deprotection or cleavage 
from resin or solid phase support of the product is possible and (2) 
introduction of the chelator to macromolecular structures such as 
dendrimer wherein this is accomplished in organic solvents eliminating 
the gross inefficiency of the prior aqueous methods.
    The compounds described in the present technology have several 
applications. All the compounds are useful in the conjugation of nearly 
all peptides, and antibodies for targeting antigens/peptides associated 
with cancers. Additionally, the compounds are useful for modification 
of macromolecules such as dendrimer, carbon tubes, etc., for labeling 
with radioactive metal ions suitable for imaging and/or therapy and 
paramagnetics for magnetic resonance imaging (MRI).

Competitive Advantage of Our Technology

    It is estimated that the demand for medical imaging products will 
expand 3.9 percent annually to $15 billion in 2010. The market for 
contrast media, radiopharmaceuticals, and other consumables and 
accessories will total $4.6 billion in 2010. Radiopharmaceuticals will 
provide the best growth opportunities as advances in biotechnology and 
nanotechnology expand the availability of safe and effective compounds 
and extend the range of diseases and disorders that can be studied 
through nuclear medicine. Additionally, the market of the contrast 
reagents and media used in radiopharmaceuticals will also see a rise in 
demand.
    Our technologies have several advantages over the existing reagents 
used as contrast agents and in metal complexes. (1) The chemistry is 
very flexible and provides the basis for an extensive list of 
conjugation functional groups to be introduced; (2) The elimination of 
aqueous chemistry steps in synthesizing the 1B4M-DTPA molecules 
obviates the possibilities of contamination by spurious metals that 
could compromise subsequent radiolabeling; (3) Furthermore, the 
elimination of aqueous steps aids in the introduction of paramagnetic 
ions such as Gd(III) for MRI applications. (4) The DOTA derivatives are 
very stable in vivo; (5) The NOTA derivatives have improved stability, 
and faster kinetics of conjugation than either DOTA or DTPA; and (6) 
The general synthesis process provides a procedure for preparing 
dendrimer-based MR agents with higher yields and efficiency while 
enhancing versatility.

Patent Estate

    This technology consists of the following patents and patent 
applications:
    1. U.S. Patent Application Serial No. 10/525,673 filed April 18, 
2005, entitled ``Backbone-Substituted Bifunctional Dota Ligands, 
Complexes And Compositions Thereof, And Methods Of Using Same'' [pub.# 
20060165600];
    2. U.S. Patent Serial No. 7,163,935 issued January 16, 2007 
entitled ``Scorpionate-Like Pendant Macrocyclic Ligands, Complexes And 
Compositions Thereof, And Methods Of Using Same'';
    3. U.S. Patent Serial No. 7,081,452 issued July 25, 2006 entitled 
``Scorpionate-Like Pendant Macrocyclic Ligands, Complexes And 
Compositions Thereof, And Methods Of Using Same''; and
    4. U.S. Provisional Patent Application 60/864,503 filed November 
06, 2006 entitled ``Method Of Preparing Macromolecular Contrast Agents 
And Uses Thereof''.
    5. PCT/US2005/028125 filed August 9, 2005 entitled ``Metal 
Chelators And Methods Of Their Use''.

Next Step: Teleconference

    There will be a teleconference where the principal investigator 
will explain this technology. Licensing and collaborative research 
opportunities will also be discussed. If you are interested in 
participating in this teleconference please call or e-mail Mojdeh 
Bahar; (301) 435-2950; [email protected]. OTT will then e-mail you 
the date, time and number for the teleconference.

    Dated: September 14, 2007.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E7-18771 Filed 9-21-07; 8:45 am]
BILLING CODE 4140-01-P